Ocular implant made by a double extrusion process

ABSTRACT

The invention provides biodegradable implants sized for implantation in an ocular region and methods for treating medical conditions of the eye. The implants are formed from a mixture of hydrophilic end and hydrophobic end PLGA, and deliver active agents into an ocular region without a high burst release.

CROSS REFERENCE

This application is a continuation in part of U.S. patent applicationSer. No. 10/340,237, filed Jan. 9, 2003, the entire contents of which isincorporated herein by reference.

BACKGROUND

This invention relates to implants and methods for treating an ocularcondition. In particular the present invention relates to implants andmethods for treating an ocular condition by implanting into an ocularregion or site a bioerodible implant comprising an active agent and abioerodible polymer matrix, wherein the implant is made by a doubleextrusion process. The bioerodible implants of this invention havevarying and extended release rates to provide for improved kinetics ofrelease of one or more active (therapeutic) agents over time.

An ocular condition can include a disease, aliment or condition whichaffects or involves the eye or one of the parts or regions of the eye.Broadly speaking the eye includes the eyeball and the tissues and fluidswhich constitute the eyeball, the periocular muscles (such as theoblique and rectus muscles) and the portion of the optic nerve which iswithin or adjacent to the eyeball. An anterior ocular condition is adisease, ailment or condition which affects or which involves ananterior (i.e. front of the eye) ocular region or site, such as aperiocular muscle, an eye lid or an eye ball tissue or fluid which islocated anterior to the posterior wall of the lens capsule or ciliarymuscles. Thus, an anterior ocular condition primarily affects orinvolves, the conjunctiva, the cornea, the conjunctiva, the anteriorchamber, the iris, the posterior chamber (behind the retina but in frontof the posterior wall of the lens capsule), the lens or the lens capsuleand blood vessels and nerve which vascularize or innervate an anteriorocular region or site. A posterior ocular condition is a disease,ailment or condition which primarily affects or involves a posteriorocular region or site such as choroid or sclera (in a position posteriorto a plane through the posterior wall of the lens capsule), vitreous,vitreous chamber, retina, optic nerve (i.e. the optic disc), and bloodvessels and nerves which vascularize or innervate a posterior ocularregion or site.

Thus, a posterior ocular condition can include a disease, ailment orcondition, such as for example, macular degeneration (such asnon-exudative age related macular degeneration and exudative age relatedmacular degeneration); choroidal neovascularization; acute macularneuroretinopathy; macular edema (such as cystoid macular edema anddiabetic macular edema); Behcet's disease, retinal disorders, diabeticretinopathy (including proliferative diabetic retinopathy); retinalarterial occlusive disease; central retinal vein occlusion; uveiticretinal disease; retinal detachment; ocular trauma which affects aposterior ocular site or location; a posterior ocular condition causedby or influenced by an ocular laser treatment; posterior ocularconditions caused by or influenced by a photodynamic therapy;photocoagulation; radiation retinopathy; epiretinal membrane disorders;branch retinal vein occlusion; anterior ischemic optic neuropathy;non-retinopathy diabetic retinal dysfunction, retinitis pigmentosa andglaucoma. Glaucoma can be considered a posterior ocular conditionbecause the therapeutic goal is to prevent the loss of or reduce theoccurrence of loss of vision due to damage to or loss of retinal cellsor optic nerve cells (i.e. neuroprotection).

An anterior ocular condition can include a disease, ailment orcondition, such as for example, aphakia; pseudophakia; astigmatism;blepharospasm; cataract; conjunctival diseases; conjunctivitis; cornealdiseases;, corneal ulcer; dry eye syndromes; eyelid diseases; lacrimalapparatus diseases; lacrimal duct obstruction; myopia; presbyopia; pupildisorders; refractive disorders and strabismus. Glaucoma can also beconsidered to be an anterior ocular condition because a clinical goal ofglaucoma treatment can be to reduce a hypertension of aqueous fluid inthe anterior chamber of the eye (i.e. reduce intraocular pressure).

The present invention is concerned with and directed to an implant andmethods for the treatment of an ocular condition, such as an anteriorocular condition or a posterior ocular condition or to an ocularcondition which can be characterized as both an anterior ocularcondition and a posterior ocular condition.

Therapeutic compounds useful for the treatment of an ocular conditioncan include active agents with, for example, an anti-neoplastic,anti-angiogenesis, kinase inhibition, anticholinergic, anti-adrenergicand/or anti-inflammatory activity.

Macular degeneration, such as age related macular degeneration (“AMD”)is a leading cause of blindness in the world. It is estimated thatthirteen million Americans have evidence of macular degeneration.Macular degeneration results in a break down the macula, thelight-sensitive part of the retina responsible for the sharp, directvision needed to read or drive. Central vision is especially affected.Macular degeneration is diagnosed as either dry (atrophic) or wet(exudative). The dry form of macular degeneration is more common thanthe wet form of macular degeneration, with about 90% of AMD patientsbeing diagnosed with dry AMD. The wet form of the disease usually leadsto more serious vision loss. Macular degeneration can produce a slow orsudden painless loss of vision. The cause of macular degeneration is notclear. The dry form of AMD may result from the aging and thinning ofmacular tissues, depositing of pigment in the macula, or a combinationof the two processes. With wet AMD, new blood vessels grow beneath theretina and leak blood and fluid. This leakage causes retinal cells todie and creates blind spots in central vision.

Macular edema (“ME”) can result in a swelling of the macula. The edemais caused by fluid leaking from retinal blood vessels. Blood leaks outof the weak vessel walls into a very small area of the macula which isrich in cones, the nerve endings that detect color and from whichdaytime vision depends. Blurring then occurs in the middle or just tothe side of the central visual field. Visual loss can progress over aperiod of months. Retinal blood vessel obstruction, eye inflammation,and age-related macular degeneration have all been associated withmacular edema. The macula may also be affected by swelling followingcataract extraction. Symptoms of ME include blurred central vision,distorted vision, vision tinted pink and light sensitivity. Causes of MEcan include retinal vein occlusion, macular degeneration, diabeticmacular leakage, eye inflammation, idiopathic central serouschorioretinopathy, anterior or posterior uveitis, pars planitis,retinitis pigmentosa, radiation retinopathy, posterior vitreousdetachment, epiretinal membrane formation, idiopathic juxtafovealretinal telangiectasia, Nd:YAG capsulotomy or iridotomy. Some patientswith ME may have a history of use of topical epinephrine orprostaglandin analogs for glaucoma. The first line of treatment for MEis typically anti-inflammatory drops topically applied.

Macular edema is a non-specific response of the retina to a variety ofinsults. It is associated with a number of diseases, including uveitis,retinal vascular abnormalities (diabetic retinopathy and retinal veinocclusive disease), a sequelae of cataract surgery (post-cataractcystoid macular oedema), macular epiretinal membranes, and inherited oracquired retinal degeneration. Macular edema involves the breakdown ofthe inner blood retinal barrier at the level of the capillaryendothelium, resulting in abnormal retinal vascular permeability andleakage into the adjacent retinal tissues. The macula becomes thickeneddue to fluid accumulation resulting in significant disturbances invisual acuity (Ahmed I, Ai E. Macular disorders: cystoid macular oedema.In: Yanoff M, Duker J S, eds. Ophthalmology. London: Mosby; 1999:34;Dick J, Jampol L M, Haller J A. Macular edema. In: Ryan S, Schachat A P,eds. Retina. 3rd ed. St. Louis, Mo.: C V Mosby; 2001, v2, Section 2 chap57:967-979).

Macular edema may occur in diseases causing cumulative injury over manyyears, such as diabetic retinopathy, or as a result of more acuteevents, such as central retinal vein occlusion or branch retinal veinocclusion.

In some cases macular edema resolves spontaneously or with short-termtreatment. Therapeutic choices for macular oedema depend on the causeand severity of the condition. Currently there are no approvedpharmacological therapies for macular edema. Focal/grid laserphotocoagulation has been shown to be efficacious in the prevention ofmoderate visual loss for macular oedema due to diabetic retinopathy(Akduman L, Olk R S. The early treatment diabetic retinopathy study. In:Kertes P S, Conway M D, eds. Clinical trials in ophthalmology: a summaryand practice guide. Baltimore, Md.: Lippincott Williams & Wilkins;1998:15-35; Frank R N. Etiologic mechanisms in diabetic retinopathy. In:Ryan S, Schachat A P, eds. Retina. 3rd ed. St. Louis, Mo.: C V Mosby;2001, v2, Section 2, chap 71:1259-1294). Argon laser photocoagulationincreased the likelihood of vision improvement in patients with macularoedema due to branch retinal vein occlusion (BRVO) (Orth D. The branchvein occlusion study. In: Kertes P. Conway M, eds. Clinical trials inophthalmology: a summary and practice guide. Baltimore, Md.: LippincottWilliams & Wilkins; 1998:113-127; Fekrat S, Finkelstein D. The CentralVein Occlusion Study. In: Kertes P S, Conway M D, eds. Clinical trialsin ophthalmology: a summary and practice guide. Baltimore, Md.:Lippincott Williams & Wilkins; 1998:129-143), but not in patients withmacular oedema due to central retinal vein occlusion (CRVO) (Fekrat andFinkelstein 1998, supra; Clarkson J G Central retinal vein occlusion.In: Ryan S, Schachat A P, eds. Retina. 3rd ed. St. Louis, Mo.: C VMosby; 2001, v2, chap 75:1368-1375). For CRVO, there are no knowneffective therapies.

An anti-inflammatory (i.e. immunosuppressive) agent can be used for thetreatment of an ocular condition, such as a posterior ocular condition,which involves inflammation, such as an uveitis or macula edema. Thus,topical or oral glucocorticoids have been used to treat uveitis. A majorproblem with topical and oral drug administration is the inability ofthe drug to achieve an adequate (i.e. therapeutic) intraocularconcentration. See e.g. Bloch-Michel E. (1992). Opening address:intermediate uveitis, In Intermediate Uveitis, Dev. Ophthalmol, W. R. F.Böke et al. editors., Basel: Karger, 23:1-2; Pinar, V., et al. (1997).Intraocular inflammation and uveitis” In Basic and Clinical ScienceCourse. Section 9 (1997-1998) San Francisco: American Academy ofOphthalmology, pp. 57-80, 102-103, 152-156; Böke, W. (1992). Clinicalpicture of intermediate uveitis, In Intermediate Uveitis, Dev.Ophthalmol. W. R. F. Böke et al. editors., Basel: Karger, 23:20-7; andCheng C-K et al. (1995). Intravitreal sustained-release dexamethasonedevice in the treatment of experimental uveitis, Invest. Ophthalmol.Vis. Sci. 36:442-53.

Systemic glucocorticoid administration can be used alone or in additionto topical glucocorticoids for the treatment of uveitis. However,prolonged exposure to high plasma concentrations (administration of 1mg/kg/day for 2-3 weeks) of steroid is often necessary so thattherapeutic levels can be achieved in the eye.

Unfortunately, these high drug plasma levels commonly lead to systemicside effects such as hypertension, hyperglycemia, increasedsusceptibility to infection, peptic ulcers, psychosis, and othercomplications. Cheng C-K et al. (1995). Intravitreal sustained-releasedexamethasone device in the treatment of experimental uveitis, Invest.Ophthalmol. Vis. Sci. 36:442-53; Schwartz, B. (1966). The response ofocular pressure to corticosteroids, Ophthalmol. Clin. North Am.6:929-89; Skalka, H. W. et al. (1980). Effect of corticosteroids oncataractformation, Arch Ophthalmol 98:1773-7; and Renfro, L. et al.(1992). Ocular effects of topical and systemic steroids, DermatologicClinics 10:505-12.

Additionally, delivery to the eye of a therapeutic amount of an activeagent can be difficult, if not impossible, for drugs with short plasmahalf-lives since the exposure of the drug to intraocular tissues islimited. Therefore, a more efficient way of delivering a drug to treat aposterior ocular condition is to place the drug directly in the eye,such as directly into the vitreous. Maurice, D. M. (1983).Micropharmaceutics of the eye, Ocular Inflammation Ther. 1:97-102; Lee,V. H. L. et al. (1989). Drug delivery to the posterior segment” Chapter25 In Retina. T. E. Ogden and A. P. Schachat eds., St. Louis: C V Mosby,Vol. 1, pp. 483-98; and Olsen, T. W. et al. (1995). Humanscleralpermeability: effects of age, cryotherapy, transscleral diodelaser, and surgical thinning, Invest. Ophthalmol. Vis. Sci.36:1893-1903.

Techniques such as intravitreal injection of a drug have shown promisingresults, but due to the short intraocular half-life of active agent,such as glucocorticoids (approximately 3 hours), intravitreal injectionsmust be frequently repeated to maintain a therapeutic drug level. Inturn, this repetitive process increases the potential for side effectssuch as retinal detachment, endophthalmitis, and cataracts. Maurice, D.M. (1983). Micropharmaceutics of the eye, Ocular Inflammation Ther.1:97-102; Olsen, T. W. et al. (1995). Human scleral permeability:effects of age, cryotherapy, transscleral diode laser, and surgicalthinning, Invest. Ophthalmol. Vis. Sci. 36:1893-1903; and Kwak, H. W.and D'Amico, D. J. (1992). Evaluation of the retinal toxicity andpharmacokinetics of dexamethasone after intravitreal injection, Arch.Ophthalmol. 110:259-66.

Additionally, topical, systemic, and periocular glucocorticoid treatmentmust be monitored closely due to toxicity and the long-term side effectsassociated with chronic systemic drug exposure sequelae. Rao, N. A. etal. (1997). Intraocular inflammation and uveitis, In Basic and ClinicalScience Course. Section 9 (1997-1998) San Francisco: American Academy ofOphthalmology, pp. 57-80, 102-103, 152-156; Schwartz, B. (1966). Theresponse of ocular pressure to corticosteroids, Ophthalmol Clin North Am6:929-89; Skalka, H. W. and Pichal, J. T. (1980). Effect ofcorticosteroids on cataract formation, Arch Ophthalmol 98:1773-7;Renfro, L and Snow, J. S. (1992). Ocular effects of topical and systemicsteroids, Dermatologic Clinics 10:505-12; Bodor, N. et al. (1992). Acomparison of intraocular pressure elevating activity of loteprednoletabonate and dexamethasone in rabbits, Current Eye Research 11:525-30.

U.S. Pat. No. 6,217,895 discusses a method of administering acorticosteroid to the posterior segment of the eye, but does notdisclose a bioerodible implant.

U.S. Pat. No. 5,501,856 discloses controlled release pharmaceuticalpreparations for intraocular implants to be applied to the interior ofthe eye after a surgical operation for disorders in retina/vitreous bodyor for glaucoma.

U.S. Pat. No. 5,869,079 discloses combinations of hydrophilic andhydrophobic entities in a biodegradable sustained release implant, anddescribes a polylactic acid polyglycolic acid (PLGA) copolymer implantcomprising dexamethasone. As shown by in vitro testing of the drugrelease kinetics, the 100-120 μg 50/50 PLGA/dexamethasone implantdisclosed did not show appreciable drug release until the beginning ofthe fourth week, unless a release enhancer, such as HPMC was added tothe formulation.

U.S. Pat. No. 5,824,072 discloses implants for introduction into asuprachoroidal space or an avascular region of the eye, and describes amethylcellulose (i.e. non-biodegradable) implant comprisingdexamethasone. WO 9513765 discloses implants comprising active agentsfor introduction into a suprachoroidal or an avascular region of an eyefor therapeutic purposes.

U.S. Pat. No. 4,997,652 and 5,164,188 disclose biodegradable ocularimplants comprising microencapsulated drugs, and describes implantingmicrocapsules comprising hydrocortisone succinate into the posteriorsegment of the eye.

U.S. Pat. No. 5,164,188 discloses encapsulated agents for introductioninto the suprachoroid of the eye, and describes placing microcapsulesand plaques comprising hydrocortisone into the pars plana. U.S. Pat.Nos. 5,443,505 and 5,766,242 discloses implants comprising active agentsfor introduction into a suprachoroidal space or an avascular region ofthe eye, and describes placing microcapsules and plaques comprisinghydrocortisone into the pars plana.

Zhou et al. disclose a multiple-drug implant comprising 5-fluorouridine,triamcinolone, and human recombinant tissue plasminogen activator forintraocular management of proliferative vitreoretinopathy (PVR). Zhou,T, et al. (1998). Development of a multiple-drug delivery implant forintraocular management of proliferative vitreoretinopathy, Journal ofControlled Release 55: 281-295.

U.S. Pat. No. 6,046,187 discusses methods and compositions formodulating local anesthetic by administering one or moreglucocorticosteroid agents before, simultaneously with or after theadministration of a local anesthetic at a site in a patient.

U.S. Pat. No. 3,986,510 discusses ocular inserts having one or moreinner reservoirs of a drug formulation confined within a bioerodibledrug release rate controlling material of a shape adapted for insertionand retention in the “sac of the eye,” which is indicated as beingbounded by the surfaces of the bulbar conjuctiva of the sclera of theeyeball and the palpebral conjunctiva of the eyelid, or for placementover the corneal section of the eye.

U.S. Pat. No. 6,369,116 discusses an implant with a release modifierinserted in a scleral flap.

EP 0 654256 discusses use of a scleral plug after surgery on a vitreousbody, for plugging an incision.

U.S. Pat. No. 4,863,457 discusses the use of a bioerodible implant toprevent failure of glaucoma filtration surgery by positioning theimplant either in the subconjunctival region between the conjunctivalmembrane overlying it and the sclera beneath it or within the scleraitself within a partial thickness sclera flap.

EP 488 401 discusses intraocular implants, made of certain polylacticacids, to be applied to the interior of the eye after a surgicaloperation for disorders of the retina/vitreous body or for glaucoma.

EP 430539 discusses use of a bioerodible implant which is inserted inthe suprachoroid.

U.S. Pat. No. 6,726,918 discusses implants for treating inflammationmediated conditions of the eye.

Significantly, it is known that PLGA co-polymer formulations of abioerodible polymer comprising an active agent typically release theactive agent with a characteristic sigmoidal release profile (as viewedas time vs percent of total active agent released), that is after arelatively long initial lag period (the first release phase) when littleif any active agent is released, there is a high positive slope periodwhen most of the active agent is released (the second release phase)followed by another near horizontal (third) release phase, when the drugrelease reaches a plateau.

One of the alternatives to intravitreal injection to administer drugs isthe placement of biodegradable implants under the sclera or into thesubconjunctival or suprachoroidal space, as described in U.S. Pat. No.4,863,457 to Lee; WO 95/13765 to Wong et al.; WO 00/37056 to Wong etal.; EP 430,539 to Wong; in Gould et al., Can. J. Ophthalmol.29(4):168-171 (1994); and in Apel et al., Curr. Eye Res. 14:659-667(1995).

Furthermore, the controlled release of drugs frompolylactide/polyglycolide (PLGA) copolymers into the vitreous has beendisclosed, e.g., in U.S. Pat. No. 5,501,856 to Ohtori et al. and EP654,256 to Ogura.

Recent experimental work has demonstrated that uncapped PLGA degradesfaster than capped (end-capped) PLGA (Park et al., J. Control. Rel.55:181-191 (1998); Tracy et al., Biomaterials 20:1057-1062 (1999); andJong et al., Polymer 42:2795-2802 (2001). Accordingly, implantscontaining mixtures of uncapped and capped PLGA have been formed tomodulate drug release. For example, U.S. Pat. No. 6,217,911 to Vaughn etal. ('911) and U.S. Pat. No. 6,309,669 to Setterstrom et al. ('669)disclose the delivery of drugs from a blend of uncapped and capped PLGAcopolymer to curtail initial burst release of the drugs. In the '911patent, the composition delivers non-steroidal anti-inflammatory drugsfrom PLGA microspheres made by a solvent extraction process or PLGAmicrocapsules prepared by a solvent evaporation process over a durationof 24 hours to 2 months. In the '669 patent, the composition deliversvarious pharmaceuticals from PLGA microcapsules over a duration of 1-100days. The PLGA microspheres or microcapsules are administered orally oras an aqueous injectable formulation. As mentioned above, there is poorpartitioning of drug into the eye with oral administration. Furthermore,use of an aqueous injectable drug composition (for injecting into theeye) should be avoided since the eye is a closed space (limited volume)with intraocular pressure ranges that are strictly maintained.Administration of an injectable may increase intraocular volume to apoint where intraocular pressures would then become pathologic.

Potent corticosteroids such as dexamethasone suppress inflammation byinhibiting edema, fibrin deposition, capillary leakage and phagocyticmigration, all key features of the inflammatory response.Corticosteroids prevent the release of prostaglandins, some of whichhave been identified as mediators of cystoid macular oedema (Leopold IH. Nonsteroidal and steroidal anti-inflammatory agents. In: Sears M,Tarkkanen A, eds. Surgical pharmacology of the eye. New York, N.Y.:Raven Press; 1985:83-133; Tennant J L. Cystoid maculopathy: 125prostaglandins in ophthalmology. In: Emery J M, ed. Current concepts incataract surgery: selected proceedings of the fifth biennial cataractsurgical congress, Section 3. St. Louis, Mo.: C V Mosby; 1978;360-362).Additionally, corticosteroids including dexamethasone have been shown toinhibit the expression of vascular endothelial growth factor (VEGF), acytokine which is a potent promoter of vascular permeability (Nauck M,Karakiulakis G. Perruchoud A P, Papakonstantinou E, Roth M.Corticosteroids inhibit the expression of the vascular endothelialgrowth factor gene in human vascular smooth muscle cells. Eur JPharmacol 1998;341:309-315).

The use of dexamethasone to date, by conventional routes ofadministration, has yielded limited success in treating retinaldisorders, including macular oedema, largely due to the inability todeliver and maintain adequate quantities of the drug to the posteriorsegment without resultant toxicity. After topical administration ofdexamethasone, only about 1% reaches the anterior segment, and only afraction of that amount moves into the posterior segment (Lee V H L,Pince K J, Frambach D A, Martini B. Drug delivery to the posteriorsegment. In: Ogden T E, Schachat A P, eds. Retina. St. Louis, Mo.: C VMosby, 1989, chap 25:483-498). Although intravitreal injections ofdexamethasone have been used, the exposure to the drug is very brief asthe half-life of the drug within the eye is approximately 3 hours(Peyman G A, Herbst R. Bacterial endophthalmitis. Arch Ophthalmol1974;91 :416-418). Periocular and posterior sub-Tenon's injections ofdexamethasone also have a short term treatment effect (Riordan-Eva P,Lightman S. Orbital floor steroid injections in the treatment ofuveitis. Eye 1994;8 (Pt 1):66-69; Jennings T, Rusin M, Tessler H,Cunha-Vaz J. Posterior sub-Tenon's injections of corticosteroids inuveitis patients with cystoid macular edema. Jpn J Ophthalmol1988;32:385-391).

Adverse reactions listed for conventional ophthalmic dexamethasonepreparations include: ocular hypertension, glaucoma, posteriorsubcapsular cataract formation, and secondary ocular infection frompathogens including herpes simplex (Lee et al, 1989 supra; Skalka H W,Prchal J T. Effect of corticosteroids on cataract formation. ArchOphthalmol 1980;98:1773-1777; Renfro L, Snow J S. Ocular effects oftopical and systemic steroids. Dermatol Clin 1992;10(3):505-512;Physician's Desk Reference, 2003). Systemic doses are associated withadditional hazardous side-effects including hypertension,hyperglycemias, increased susceptibility to infection, and peptic ulcers(Physician's Desk Reference, 2003).

By delivering a drug directly into the vitreous cavity, blood eyebarriers can be circumvented and intraocular therapeutic levels can beachieved with minimal risk of systemic toxicity (Lee et al, 1989 supra).This route of administration typically results in a short half-lifeunless the drug can be delivered using a formulation capable ofproviding sustained release.

Consequently, a biodegradable implant for delivering a therapeutic agentto an ocular region may provide significant medical benefit for patientsafflicted with a medical condition of the eye.

DRAWINGS

FIG. 1 shows the in vivo concentration of dexamethasone in the vitreousof rabbit eyes over a 42 day period after implantation of compressed andextruded biodegradable implants containing 350 μg dexamethasone into theposterior segment of rabbit eyes.

FIG. 2 shows the in vivo cumulative percentage release of dexamethasonein the vitreous of rabbit eyes over a 42 day period after implantationof compressed and extruded biodegradable implants containing 350 μgdexamethasone and 700 μg dexamethasone into the posterior segment ofrabbit eyes.

FIG. 3 shows the in vivo concentration of dexamethasone in the aqueoushumor of rabbit eyes over a 42 day period after implantation ofcompressed and extruded biodegradable implants containing 350 jigdexamethasone into the posterior segment of rabbit eyes.

FIG. 4 shows the in vivo concentration of dexamethasone in the plasma(from a rabbit blood sample) over a 42 day period after implantation ofcompressed and extruded biodegradable implants containing 350 μgdexamethasone into the posterior segment of rabbit eyes.

FIG. 5 shows the in vivo concentration of dexamethasone in the vitreousof rabbit eyes over a 42 day period after implantation of compressed andextruded biodegradable implants containing 700 μg dexamethasone into theposterior segment of rabbit eyes.

FIG. 6 shows the in vivo concentration of dexamethasone in the aqueoushumor of rabbit eyes over a 42 day period after implantation ofcompressed and extruded biodegradable implants containing 700 μgdexamethasone into the posterior segment of rabbit eyes.

FIG. 7 shows the in vivo concentration of dexamethasone in the plasma(from a rabbit blood sample) over a 42 day period after implantation ofcompressed and extruded biodegradable implants containing 700 μgdexamethasone into the posterior segment of rabbit eyes.

FIG. 8 shows the in vivo concentration of dexamethasone in the vitreousof rabbit eyes over a 42 day period after implantation of compressed andextruded biodegradable implants containing 350 μg dexamethasone and 700μg dexamethasone into the posterior segment of rabbit eyes.

FIG. 9 shows the in vitro total cumulative percentage release ofdexamethasone into a saline solution at 37° C. from 60/40 w/wdexamethasone/PLGA implants having a weight ratio of 40:0 hydrophobicend to hydrophilic end PLGA (312-140-2), weight ratio of 30:10hydrophobic end to hydrophilic end PLGA (312-140-4), weight ratio of20:20 hydrophobic end to hydrophilic end PLGA (312-140-3), and weightratio of 0:40 hydrophobic end to hydrophilic end PLGA (312-140-1).

FIG. 10 compares the in vitro cumulative percentage release ofdexamethasone into a saline solution at 37° C. for six lots of extrudedimplants having 60% by weight dexamethasone, 30% by weight hydrophilicend PLGA, and 10% by weight hydrophobic end PLGA.

FIG. 11 is a flow chart illustrating manufacturing processes for tablet,single and double extrusion methods for making an ocular implant withinthe scope of the present invention.

FIG. 12 is a graph which shows the cumulative amount of dexamethasonereleased in vitro over time for an ocular implant made by eithertabletting or a single extrusion processes.

FIG. 13 are scanning electromicrographs (SEM) pictures of DEX PS DDSimplants made by a tabletting process and by a single extrusion process.

FIG. 14 shows two graphs of batch to batch vs within batch variabilityof % LC (% of total dexamethasone) for implants made from eitherunmilled or milled PLGAs.

FIG. 15 is a graph showing in vitro release of dexamethasone from DEX PSDDS implants made by either a single extrusion or by a double extrusionprocess.

FIG. 16 is a flow chart illustrating a double extrusion manufacturingprocesses for making an ocular implant within the scope of the presentinvention.

FIG. 17 provides a cut-away side view of an applicator to implant anocular implant within the scope of the present invention.

SUMMARY

Definitions

The following terms as used herein have the following meanings:

“About” means approximately or nearly and in the context of a numericalvalue or range set forth herein means±10% of the numerical value orrange recited or claimed.

“Active agent” and “drug” are used interchangeably and refer to anysubstance used to treat an ocular condition.

“Bioerodible polymer” means a polymer which degrades in vivo, andwherein erosion of the polymer over time is required to achieve theactive agent release kinetics according to the present invention. Thus,hydrogels such as methylcellulose which act to release drug throughpolymer swelling are specifically excluded from the term “bioerodible(or biodegradable) polymer”. The words “bioerodible” and “biodegradable”are synonymous and are used interchangeably herein.

“Concentration equivalent to dexamethasone”, or “dexamethasoneequivalent” means a concentration of an active agent, such as asteroidal anti-inflammatory agent, necessary to have approximately thesame efficacy in vivo as a particular dose of dexamethasone. Forexample, hydrocortisone is approximately twenty five fold less potentthan dexamethasone, and thus a 25 mg dose of hydrocortisone would beequivalent to a 1 mg dose of dexamethasone. One of ordinary skill in theart would be able to determine the concentration equivalent todexamethasone for a particular steroidal anti-inflammatory agent fromone of several standard tests known in the art. Relative potencies ofselected corticosteroids may be found, for example, in Gilman, A. G., etal., eds. (1990). Goodman and Gilman's: The Pharmacological Basis ofTherapeutics. 8th Edition, Pergamon Press: New York, p.1447.

“Cumulative release profile” means to the cumulative total percent of anactive agent released from an implant into an ocular region or site invivo over time or into a specific release medium in vitro over time.

“Glaucoma” means primary, secondary and/or congenital glaucoma. Primaryglaucoma can include open angle and closed angle glaucoma. Secondaryglaucoma can occur as a complication of a variety of other conditions,such as injury, inflammation, vascular disease and diabetes.

“Inflammation-mediated” in relation to an ocular condition means anycondition of the eye which can benefit from treatment with ananti-inflammatory agent, and is meant to include, but is not limited to,uveitis, macular edema, acute macular degeneration, retinal detachment,ocular tumors, fungal or viral infections, multifocal choroiditis,diabetic uveitis, proliferative vitreoretinopathy (PVR), sympatheticopthalmia, Vogt Koyanagi-Harada (VKH) syndrome, histoplasmosis, anduveal diffusion.

“Injury” or “damage” are interchangeable and refer to the cellular andmorphological manifestations and symptoms resulting from aninflammatory-mediated condition, such as, for example, inflammation.

“Measured under infinite sink conditions in vitro,” means assays tomeasure drug release in vitro, wherein the experiment is designed suchthat the drug concentration in the receptor medium never exceeds 5% ofsaturation. Examples of suitable assays may be found, for example, inUSP 23; NF 18 (1995) pp. 1790-1798.

“Ocular condition” means a disease, aliment or condition which affectsor involves the eye or one or the parts or regions of the eye, such as aretinal disease. The eye includes the eyeball and the tissues and fluidswhich constitute the eyeball, the periocular muscles (such as theoblique and rectus muscles) and the portion of the optic nerve which iswithin or adjacent to the eyeball. :“Ocular condition” is synonymouswith “medical condition of the eye”

“Plurality” means two or more.

“Posterior ocular condition” means a disease, ailment or condition whichaffects or involves a posterior ocular region or site such as choroid orsclera (in a position posterior to a plane through the posterior wall ofthe lens capsule), vitreous, vitreous chamber, retina, optic nerve (i.e.the optic disc), and blood vessels and nerve which vascularize orinnervate a posterior ocular region or site.

“Steroidal anti-inflammatory agent” and “glucocorticoid” are usedinterchangeably herein, and are meant to include steroidal agents,compounds or drugs which reduce inflammation when administered at atherapeutically effective level.

“Substantially” in relation to the release profile or the releasecharacteristic of an active agent from a bioerodible implant as in thephrase “substantially continuous rate” of the active agent release ratefrom the implant means, that the rate of release (i.e. amount of activeagent released/unit of time) does not vary by more than 100%, andpreferably does not vary by more than 50%, over the period of timeselected (i.e. a number of days). “Substantially” in relation to theblending, mixing or dispersing of an active agent in a polymer, as inthe phrase “substantially homogenously dispersed” means that there areno or essentially no particles (i.e. aggregations) of active agent insuch a homogenous dispersal.

“Suitable for insertion (or implantation) in (or into) an ocular regionor site” with regard to an implant, means an implant which has a size(dimensions) such that it can be inserted or implanted without causingexcessive tissue damage and without unduly physically interfering withthe existing vision of the patient into which the implant is implantedor inserted.

“Therapeutic levels” or “therapeutic amount” means an amount or aconcentration of an active agent that has been locally delivered to anocular region that is appropriate to safely treat an ocular condition soas to reduce or prevent a symptom of an ocular condition.

The meaning of abbreviations used herein is explained below:

Term Meaning

-   1^(H)-NMR Proton nuclear magnetic resonance-   ABS Poly acrylonitrile butadiene styrene-   ACC Anterior chamber cell-   ALT Alanine aminotransferase-   API Active pharmaceutical ingredient-   AVC Anterior vitreous cells-   BCVA Best-corrected visual acuity-   BI Boehringer Ingelheim-   BRVO Branch retinal vein occlusion-   BSE Bovine Spongiform Encephalopathy-   BVOS Branch Vein Occlusion Study-   B/N Batch number-   ° C. Degrees Centigrade-   CA California-   CAS Chemical abstract services-   CF Count fingers-   CFU Colony forming unit-   cGMP Current Good Manufacturing Practice-   CI Confidence interval-   CIB Clinical Investigator's Brochure-   CO₂ Carbon dioxide-   COEX Co-extruded-   CRVO Central retinal vein occlusion-   CVOS Central Vein Occlusion Study-   DDS Drug delivery system-   DEX Dexamethasone-   DEX PS DDS Dexamethasone posterior segment drug delivery system    (implant)-   DEX PS DDS Applicator Dexamethasone posterior segment drug delivery-   system system (medicinal product)-   DME Diabetic macular oedema-   EMEA European medicine evaluation agency-   ETDRS Early Treatment of Diabetic Retinopathy Study-   EU Endotoxin unit-   ° F. Degrees Fahrenheit-   G Gram-   GLP Good Laboratory Practice-   GRB Geographical BSE (Bovine Spongiform Encephalopathies) risk-   H₂O Water-   HDPE High density polyethylene-   HPLC High performance liquid chromatography-   IEC Independent Ethics Committee-   IMPD Investigational medicinal product dossier-   INN International Non-proprietary Name-   IOP Intraocular pressure-   IPC In process control-   IR Infrared-   IRB Institutional Review Board-   ISO International standard organisation-   Kg Kilogram-   kGy Kilo Grey-   LAF Laminar Air Flow-   LAL Limulus Amebocytes Lisat-   LC Label Claim-   LOCF Last observation carried forward-   LS Label strength-   ME Macular oedema-   μg Microgram-   Mg Milligram-   μJ Microjoules-   mL Millilitre(s)-   Mm Millimetre(s)-   mmHg Millimeters of mercury-   mol Mole-   n or N Number-   n/a Not applicable-   ND Not detected-   Ng Nanogram(s)-   NSAID Nonsteroidal anti-inflammatory drug-   NT Not tested-   OCT Optical Coherence Tomography-   PDE Permitted daily exposure-   PET Polyethylene terephtalate-   pH Hydrogen potential-   Ph. Eur. European Pharmacopoeia-   PK Pharmacokinetics-   pKa Acid dissociation constant-   PLGA, PLG Poly (D,L-lactide-co-glycolide).-   PME Persistent macular edema-   ppm Part per million-   PS Posterior segment-   PVR Proliferative vitreoretinopathy-   RH Relative humidity-   SAE Serious adverse event-   SD Standard deviation-   SEM Scanning electron microscope-   TSE Transmissible spongiform encephalopathy-   USA United States of America-   USP United States Pharmacopoeia-   UV Ultra violet-   VEGF Vascular endothelial growth factor-   WPE Ultrahigh molecular weight polyethylene

Our invention encompasses a bioerodible implant for treating a medicalcondition of the eye comprising an active agent dispersed within abiodegradable polymer matrix, wherein at least about 75% of theparticles of the active agent have a diameter of less than about 10 μm.Preferably, at least about 99% of the particles have a diameter of sthan about 20 μm.

The active agent can be selected from the group consisting oface-inhibitors, endogenous cytokines, agents that influence basementmembrane, agents that influence the growth of endothelial cells,adrenergic agonists or blockers, cholinergic agonists or blockers,aldose reductase inhibitors, analgesics, anesthetics, antiallergics,anti-inflammatory agents, steroids (such as a steroidalanti-inflammatory agent), antihypertensives, pressors, antibacterials,antivirals, antifungals, antiprotozoals, anti-infective agents,antitumor agents, antimetabolites, and antiangiogenic agents. Thus, theactive agent can be cortisone, dexamethasone, fluocinolone,hydrocortisone, methylprednisolone, prednisolone, prednisone,triamcinolone, and any derivative thereof.

The bioerodible implant is sized for implantation in an ocular region.Te ocular region can be any one or more of the anterior chamber, theposterior chamber, the vitreous cavity, the choroid, the suprachoroidalspace, the conjunctiva, the subconjunctival space, the episcleral space,the intracorneal space, the epicorneal space, the sclera, the parsplana, surgically-induced avascular regions, the macula, and the retina.

An alternate embodiment of the bioerodible implant can comprise asteroid active agent dispersed within a biodegradable polymer matrix,wherein at least about 75% of the particles of the active agent have adiameter of less than about 20 μm.

Our present invention also encompasses a method for making a bioerodibleimplant for treating a medical condition of the eye, the methodcomprising a plurality of extrusions of a biodegradable polymer. Thismethod can also comprise the step of milling the biodegradable polymerprior to the extrusion. The biodegradable polymer can be apoly(lactic-co-glycolic)acid (PLGA) copolymer. The ratio of lactic toglycolic acid monomers in the polymer can be about 50/50 weightpercentage. Additionally, the PLGA copolymer can be about 20 to about 90weight percent of the bioerodible implant. Alternately, the PLGAcopolymer can be about 40 percent by weight of the bioerodible implant.

A detailed method for making a bioerodible implant for treating amedical condition of the eye can have the steps of: (a) milling abiodegradable polymer; (b) blending the milled biodegradable polymer andparticles of an active agent, to thereby obtain a blended mixture of themilled biodegradable polymer and the particles of the active agent,wherein at least about 75% of the particles of the active agent have adiameter of less than about 20 μm; (c) carrying out a first extrusion ofthe blended mixture, to thereby obtain a first extrusion product; (d)pelletizing the first extrusion product, and; (e) carrying out a secondextrusion of the pelletized first extrusion product, thereby obtaining abioerodible implant for treating a medical condition of the eye. Ourinvention also includes a bioerodible implant for treating a medicalcondition of the eye made by this detailed method.

DESCRIPTION

The present invention provides biodegradable ocular implants and methodsfor treating medical conditions of the eye. Usually, the implants areformed to be monolithic, i.e., the particles of active agent aredistributed throughout the biodegradable polymer matrix. Furthermore,the implants are formed to release an active agent into an ocular regionof the eye over various time periods. The active agent may be releaseover a time period including, but is not limited to, approximately sixmonths, approximately three months, approximately one month, or lessthan one month.

Biodegradable Implants For Treating Medical Conditions of the Eye

The implants of the invention include an active agent dispersed within abiodegradable polymer. The implant compositions typically vary accordingto the preferred drug release profile, the particular active agent used,the condition being treated, and the medical history of the patient.Active agents that may be used include, but are not limited to,ace-inhibitors, endogenous cytokines, agents that influence basementmembrane, agents that influence the growth of endothelial cells,adrenergic agonists or blockers, cholinergic agonists or blockers,aldose reductase inhibitors, analgesics, anesthetics, antiallergics,anti-inflammatory agents, antihypertensives, pressors, antibacterials,antivirals, antifungals, antiprotozoals, anti-infectives, antitumoragents, antimetabolites, and antiangiogenic agents.

In one variation the active agent is methotrexate. In another variation,the active agent is retinoic acid. In a preferred variation, theanti-inflammatory agent is a nonsteroidal anti-inflammatory agent.Nonsteroidal anti-inflammatory agents that may be used include, but arenot limited to, aspirin, diclofenac, flurbiprofen, ibuprofen, ketorolac,naproxen, and suprofen. In a more preferred variation, theanti-inflammatory agent is a steroidal anti-inflammatory agent.

Steroidal Anti-Inflammatory Agents

The steroidal anti-inflammatory agents that may be used in the ocularimplants include, but are not limited to, 21-acetoxypregnenolone,alclometasone, algestone, amcinonide, beclomethasone, betamethasone,budesonide, chloroprednisone, clobetasol, clobetasone, clocortolone,cloprednol, corticosterone, cortisone, cortivazol, deflazacort,desonide, desoximetasone, dexamethasone, diflorasone, diflucortolone,difluprednate, enoxolone, fluazacort, flucloronide, flumethasone,flunisolide, fluocinolone acetonide, fluocinonide, fluocortin butyl,fluocortolone, fluorometholone, fluperolone acetate, fluprednideneacetate, fluprednisolone, flurandrenolide, fluticasone propionate,formocortal, halcinonide, halobetasol propionate, halometasone,halopredone acetate, hydrocortamate, hydrocortisone, loteprednoletabonate, mazipredone, medrysone, meprednisone, methylprednisolone,mometasone furoate, paramethasone, prednicarbate, prednisolone,prednisolone 25-diethylamino-acetate, prednisolone sodium phosphate,prednisone, prednival, prednylidene, rimexolone, tixocortol,triamcinolone, triamcinolone acetonide, triamcinolone benetonide,triamcinolone hexacetonide, and any of their derivatives.

In one variation, cortisone, dexamethasone, fluocinolone,hydrocortisone, methylprednisolone, prednisolone, prednisone, andtriamcinolone, and their derivatives, are preferred steroidalanti-inflammatory agents. In another preferred variation, the steroidalanti-inflammatory agent is dexamethasone. In another variation, thebiodegradable implant includes a combination of two or more steroidalanti-inflammatory agents.

The steroidal anti-inflammatory agent may constitute from about 10% toabout 90% by weight of the implant. In one variation, the agent is fromabout 40% to about 80% by weight of the implant. In a preferredvariation, the agent comprises about 60% by weight of the implant.

The Biodegradable Polymer Matrix

In one variation, the active agent may be homogeneously dispersed in thebiodegradable polymer matrix of the implants. The selection of thebiodegradable polymer matrix to be employed will vary with the desiredrelease kinetics, patient tolerance, the nature of the disease to betreated, and the like. Polymer characteristics that are consideredinclude, but are not limited to, the biocompatibility andbiodegradability at the site of implantation, compatibility with theactive agent of interest, and processing temperatures. The biodegradablepolymer matrix usually comprises at least about 10, at least about 20,at least about 30, at least about 40, at least about 50, at least about60, at least about 70, at least about 80, or at least about 90 weightpercent of the implant. In one variation, the biodegradable polymermatrix comprises about 40% by weight of the implant.

Biodegradable polymer matrices which may be employed include, but arenot limited to, polymers made of monomers such as organic esters orethers, which when degraded result in physiologically acceptabledegradation products. Anhydrides, amides, orthoesters, or the like, bythemselves or in combination with other monomers, may also be used. Thepolymers are generally condensation polymers. The polymers may becrosslinked or non-crosslinked. If crosslinked, they are usually notmore than lightly crosslinked, and are less than 5% crosslinked, usuallyless than 1% crosslinked.

For the most part, besides carbon and hydrogen, the polymers willinclude oxygen and nitrogen, particularly oxygen. The oxygen may bepresent as oxy, e.g., hydroxy or ether, carbonyl, e.g.,non-oxo-carbonyl, such as carboxylic acid ester, and the like. Thenitrogen may be present as amide, cyano, and amino. An exemplary list ofbiodegradable polymers that may be used are described in Heller,Biodegradable Polymers in Controlled Drug Delivery, In: “CRC CriticalReviews in Therapeutic Drug Carrier Systems”, Vol. 1. CRC Press, BocaRaton, Fla. (1987).

Of particular interest are polymers of hydroxyaliphatic carboxylicacids, either homo- or copolymers, and polysaccharides. Included amongthe polyesters of interest are homo- or copolymers of D-lactic acid,L-lactic acid, racemic lactic acid, glycolic acid, caprolactone, andcombinations thereof. Copolymers of glycolic and lactic acid are ofparticular interest, where the rate of biodegradation is controlled bythe ratio of glycolic to lactic acid. The percent of each monomer inpoly(lactic-co-glycolic)acid (PLGA) copolymer may be 0-100%, about15-85%, about 25-75%, or about 35-65%. In a preferred variation, a 50/50PLGA copolymer is used. More preferably, a random copolymer of 50/50PLGA is used.

Biodegradable polymer matrices that include mixtures of hydrophilic andhydrophobic ended PLGA may also be employed, and are useful inmodulating polymer matrix degradation rates. Hydrophobic ended (alsoreferred to as capped or end-capped) PLGA has an ester linkagehydrophobic in nature at the polymer terminus. Typical hydrophobic endgroups include, but are not limited to alkyl esters and aromatic esters.Hydrophilic ended (also referred to as uncapped) PLGA has an end grouphydrophilic in nature at the polymer terminus. PLGA with a hydrophilicend groups at the polymer terminus degrades faster than hydrophobicended PLGA because it takes up water and undergoes hydrolysis at afaster rate (Tracy et al., Biomaterials 20:1057-1062 (1999)). Examplesof suitable hydrophilic end groups that may be incorporated to enhancehydrolysis include, but are not limited to, carboxyl, hydroxyl, andpolyethylene glycol. The specific end group will typically result fromthe initiator employed in the polymerization process. For example, ifthe initiator is water or carboxylic acid, the resulting end groups willbe carboxyl and hydroxyl. Similarly, if the initiator is amonofunctional alcohol, the resulting end groups will be ester orhydroxyl.

The implants may be formed from all hydrophilic end PLGA or allhydrophobic end PLGA. In general, however, the ratio of hydrophilic endto hydrophobic end PLGA in the biodegradable polymer matrices of thisinvention range from about 10:1 to about 1:10 by weight. For example,the ratio may be 3:1, 2:1, or 1:1 by weight. In a preferred variation,an implant with a ratio of hydrophilic end to hydrophobic end PLGA of3:1 w/w is used.

Additional Agents

Other agents may be employed in the formulation for a variety ofpurposes. For example, buffering agents and preservatives may beemployed. Preservatives which may be used include, but are not limitedto, sodium bisulfite, sodium bisulfate, sodium thiosulfate, benzalkoniumchloride, chlorobutanol, thimerosal, phenylmercuric acetate,phenylmercuric nitrate, methylparaben, polyvinyl alcohol and phenylethylalcohol. Examples of buffering agents that may be employed include, butare not limited to, sodium carbonate, sodium borate, sodium phosphate,sodium acetate, sodium bicarbonate, and the like, as approved by the FDAfor the desired route of administration. Electrolytes such as sodiumchloride and potassium chloride may also be included in the formulation.

The biodegradable ocular implants may also include additionalhydrophilic or hydrophobic compounds that accelerate or retard releaseof the active agent. Furthermore, the inventors believe that becausehydrophilic end PLGA has a higher degradation rate than hydrophobic endPLGA due to its ability to take up water more readily, increasing theamount of hydrophilic end PLGA in the implant polymer matrix will resultin faster dissolution rates. FIG. 9 shows that the time fromimplantation to significant release of active agent (lag time) increaseswith decreasing amounts of hydrophilic end PLGA in the ocular implant.In FIG. 9, the lag time for implants having 0% hydrophilic end PLGA (40%w/w hydrophobic end) was shown to be about 21 days. In comparison, asignificant reduction in lag time was seen with implants having 10% w/wand 20% w/w hydrophilic end PLGA.

Release Kinetics

The inventors believe the implants of the invention are formulated withparticles of an active agent dispersed within a biodegradable polymermatrix. Without being bound by theory, the inventors believe thatrelease of the active agent is achieved by erosion of the biodegradablepolymer matrix and by diffusion of the particulate agent into an ocularfluid, e.g., the vitreous, with subsequent dissolution of the polymermatrix and release of the active agent. The inventors believe that thefactors that influence the release kinetics include such characteristicsas the size of the active agent particles, the solubility of the activeagent, the ratio of active agent to polymer(s), the method ofmanufacture, the surface area exposed, and the erosion rate of thepolymer(s). The release kinetics achieved by this form of active agentrelease are different than that achieved through formulations whichrelease active agents through polymer swelling, such as with crosslinkedhydrogels. In that case, the active agent is not released throughpolymer erosion, but through polymer swelling, which releases agent asliquid diffuses through the pathways exposed.

The inventors believe that the release rate of the active agent dependsat least in part on the rate of degradation of the polymer backbonecomponent or components making up the biodegradable polymer matrix. Forexample, condensation polymers may be degraded by hydrolysis (amongother mechanisms) and therefore any change in the composition of theimplant that enhances water uptake by the implant will likely increasethe rate of hydrolysis, thereby increasing the rate of polymerdegradation and erosion, and thus increasing the rate of active agentrelease.

The release kinetics of the implants of the invention are dependent inpart on the surface area of the implants. A larger surface area exposesmore polymer and active agent to ocular fluid, causing faster erosion ofthe polymer matrix and dissolution of the active agent particles in thefluid. The size and shape of the implant may also be used to control therate of release, period of treatment, and active agent concentration atthe site of implantation. At equal active agent loads, larger implantswill deliver a proportionately larger dose, but depending on the surfaceto mass ratio, may possess a slower release rate. For implantation in anocular region, the total weight of the implant preferably ranges, e.g.,from about 100-5000 μg, usually from about 500-1500 μg. In onevariation, the total weight of the implant is about 600 μg. In anothervariation, the total weight of the implant is about 1200 μg.

The bioerodible implants are typically solid, and may be formed asparticles, sheets, patches, plaques, films, discs, fibers, rods, and thelike, or may be of any size or shape compatible with the selected siteof implantation, as long as the implants have the desired releasekinetics and deliver an amount of active agent that is therapeutic forthe intended medical condition of the eye. The upper limit for theimplant size will be determined by factors such as the desired releasekinetics, toleration for the implant at the site of implantation, sizelimitations on insertion, and ease of handling. For example, thevitreous chamber is able to accommodate relatively large rod-shapedimplants, generally having diameters of about 0.05 mm to 3 mm and alength of about 0.5 to about 10 mm. In one variation, the rods havediameters of about 0.1 mm to about 1 mm. In another variation, the rodshave diameters of about 0.3 mm to about 0.75 mm. In yet a furthervariation, other implants having variable geometries but approximatelysimilar volumes may also be used.

As previously discussed, the release of an active agent from abiodegradable polymer matrix may also be modulated by varying the ratioof hydrophilic end PLGA to hydrophobic end PLGA in the matrix. Releaserates may be further manipulated by the method used to manufacture theimplant. For instance, as illustrated in Examples 4-7, extruded 60/40w/w dexamethasone/PLGA implants having a ratio of hydrophilic end andhydrophobic end PLGA of 3:1, compared to compressed tablet implants,demonstrate a different drug release profile and concentration of agentin the vitreous over about a one month period. Overall, a lower burst ofagent release and a more consistent level of agent in the vitreous isdemonstrated with the extruded implants.

As shown in FIG. 2 and Examples 4 and 5, a higher initial burst ofactive agent release occurs on day one after implantation with the 350μg dexamethasone compressed tablet implant (350T) in comparison to the350 μg dexamethasone extruded implant (350E). A higher initial burst ofactive agent release also occurs with the 700 μg dexamethasonecompressed implant (700T) in comparison to the 700 fig dexamethasoneextruded implant (700E) on day 1, as shown in FIG. 2 and Examples 6 and7.

The proportions of active agent, biodegradable polymer matrix, and anyother additives may be empirically determined by formulating severalimplants with varying proportions and determining the release profile invitro or in vivo. A USP approved method for dissolution or release testcan be used to measure the rate of release in vitro (USP 24; NF 19(2000) pp. 1941-1951). For example, a weighed sample of the implant isadded to a measured volume of a solution containing 0.9% NaCl in water,where the solution volume will be such that the active agentconcentration after release is less than 20% of saturation. The mixtureis maintained at 37° C. and stirred or shaken slowly to maintain theimplants in suspension. The release of the dissolved active agent as afunction of time may then be followed by various methods known in theart, such as spectrophotometrically, HPLC, mass spectroscopy, and thelike, until the solution concentration becomes constant or until greaterthan 90% of the active agent has been released.

In one variation, the extruded implants described herewith (ratio ofhydrophilic end PLGA to hydrophobic end PLGA of 3:1) may have in vivocumulative percentage release profiles with the following describedcharacteristics, as shown in FIG. 2, where the release profiles are forrelease of the active agent in vivo after implantation of the implantsinto the vitreous of rabbit eyes. The volume of rabbit eyes isapproximately 60-70% of human eyes.

At day one after implantation, the percentage in vivo cumulative releasemay be between about 0% and about 15%, and more usually between about 0%and about 10%. At day one after implantation, the percentage in vivocumulative release may be less than about 15%, and more usually lessthan about 10%.

At day three after implantation, the percentage in vivo cumulativerelease may be between about 0% and about 20%, and more usually betweenabout 5% and about 15%. At day three after implantation, the percentagein vivo cumulative release may be less than about 20%, and more usuallyless than about 15%.

At day seven after implantation, the percentage in vivo cumulativerelease may be between about 0% and about 35%, more usually betweenabout 5% and about 30%, and more usually still between about 10% andabout 25%. At day seven after implantation, the percentage in vivocumulative release may be greater than about 2%, more usually greaterthan about 5%, and more usually still greater than about 10%.

At day fourteen after implantation, the percentage in vivo cumulativerelease may be between about 20% and about 60%, more usually betweenabout 25% and about 55%, and more usually still between about 30% andabout 50%. At day fourteen after implantation, the percentage in vivocumulative release may be greater than about 20%, more usually greaterthan about 25%, and more usually still greater than about 30%.

At day twenty-one after implantation, the percentage in vivo cumulativerelease may be between about 55% and about 95%, more usually betweenabout 60% and about 90%, and more usually still between about 65% andabout 85%. At day twenty-one after implantation, the percentage in vivocumulative release may be greater than about 55%, more usually greaterthan about 60%, and more usually still greater than about 65%.

At day twenty-eight after implantation, the percentage in vivocumulative release may be between about 80% and about 100%, more usuallybetween about 85% and about 100%, and more usually still between about90% and about 100%. At day twenty-eight after implantation, thepercentage in vivo cumulative release may be greater than about 80%,more usually greater than about 85%, and more usually still greater thanabout 90%.

At day thirty-five after implantation, the percentage in vivo cumulativerelease may be between about 95% and about 100%, and more usuallybetween about 97% and about 100%. At day thirty-five after implantation,the percentage in vivo cumulative release may be greater than about 95%,and more usually greater than about 97%.

In one variation, the percentage in vivo cumulative release has thefollowing characteristics: one day after implantation it is less thanabout 15%; three days after implantation it is less than about 20%;seven days after implantation it is greater than about 5%; fourteen daysafter implantation it is greater than about 25%; twenty-one days afterimplantation it is greater than about 60%; and twenty-eight days afterimplantation it is greater than about 80%. In another variation, thepercentage in vivo cumulative release has the following characteristics:one day after implantation it is less than about 10%; three days afterimplantation it is less than about 15%; seven days after implantation itis greater than about 10%; fourteen days after implantation it isgreater than about 30%; twenty-one days after implantation it is greaterthan about 65%; twenty-eight days after implantation it is greater thanabout 85%.

In yet another variation, the extruded implants described in this patentmay have in vitro cumulative percentage release profiles in salinesolution at 37° C. with the following characteristics, as furtherdescribed below, and as shown in FIG. 10.

The percentage in vitro cumulative release at day one may be betweenabout 0% and about 5%, and more usually between about 0% and about 3%.The percentage in vitro cumulative release at day one may be less thanabout 5%, and more usually less than about 3%.

The percentage in vitro cumulative release at day four may be betweenabout 0% and about 7%, and more usually between about 0% and about 5%.The percentage in vitro cumulative release at day four may be less thanabout 7%, and more usually less than about 5%.

The percentage in vitro cumulative release at day seven may be betweenabout 1% and about 10%, and more usually between about 2% and about 8%.The percentage in vitro cumulative release at day seven may be greaterthan about 1%, and more usually greater than about 2%.

The percentage in vitro cumulative release at day 14 may be betweenabout 25% and about 65%, more usually between about 30% and about 60%,and more usually still between about 35% and about 55%. The percentagein vitro cumulative release at day 14 may be greater than about 25%,more usually greater than about 30%, and more usually still greater thanabout 35%.

The percentage in vitro cumulative release at day 21 may be betweenabout 60% and about 100%, more usually between about 65% and about 95%,and more usually still between about 70% and about 90%. The percentagein vitro cumulative release at day 21 may be greater than about 60%,more usually greater than about 65%, and more usually still greater thanabout 70%.

The percentage in vitro cumulative release at day 28 may be betweenabout 75% and about 100%, more usually between about 80% and about 100%,and more usually still between about 85% and about 95%. The percentagein vitro cumulative release at day 28 may be greater than about 75%,more usually greater than about 80%, and more usually still greater thanabout 85%.

The percentage in vitro cumulative release at day 35 may be betweenabout 85% and about 100%, more usually between about 90% and about 100%,and more usually still between about 95% and about 100%. The percentagein vitro cumulative release at day 35 may be greater than about 85%,more usually greater than about 90%, and more usually still greater thanabout 95%.

In one variation, the percentage in vitro cumulative release has thefollowing characteristics: after one day it is less than about 1%; afterfour days it is less than about 7%; after seven days it is greater thanabout 2%; after 14 days it is greater than about 30%; after 21 days itis greater than about 65%; after 28 days it is greater than about 80%;and after 35 days it is greater than about 90%. In another variation,the percentage in vitro cumulative release has the followingcharacteristics: after one day it is less than about 3%; after four daysit is less than about 5%; after seven days it is greater than about 2%;after 14 days it is greater than about 35%; after 21 days it is greaterthan about 70%; after 28 days it is greater than about 85%; and after 35days it is greater than about 90%.

Besides showing a lower burst effect for the extruded implants, FIGS. 2and 10 also demonstrate that after 28 days in vivo in rabbit eyes, or invitro in a saline solution at 37° C., respectively, almost all of theactive agent has been released from the implants. Furthermore, FIGS. 2and 10 show that the active agent release profiles for the extrudedimplants in vivo (from the time of implantation) and in vitro (from thetime of placement into a saline solution at 37° C.) are substantiallysimilar and follow approximately a sigmoidal curve, releasingsubstantially all of the active agent over 28 days. From day one toapproximately day 17, the curves show approximately an upward curvature(i.e., the derivative of the curve increases as time increases), andfrom approximately day 17 onwards the curves show approximately adownward curvature (i.e., the derivative of the curve decreases as timeincreases).

In contrast, the plots shown in FIG. 2 for the 350 μg and 700 μgdexamethasone compressed tablet implants exhibit a higher initial burstof agent release generally followed by a gradual increase in release.Furthermore, as shown in FIGS. 1 and 5, implantation of a compressedimplant results in different concentrations of active agent in thevitreous at various time points from implants that have been extruded.For example, as shown in FIGS. 1 and 5, with extruded implants there isa gradual increase, plateau, and gradual decrease in intravitreal agentconcentrations. In contrast, for compressed tablet implants, there is ahigher initial active agent release followed by an approximatelyconstant decrease over time. Consequently, the intravitrealconcentration curve for extruded implants results in more sustainedlevels of active agent in the ocular region.

In addition to the previously described implants releasing substantiallyall of the therapeutic agent within 35 days, by varying implantcomponents including, but not limited to, the composition of thebiodegradable polymer matrix, implants may also be formulated to releasea therapeutic agent for any desirable duration of time, for example, forabout one week, for about two weeks, for about three weeks, for aboutfour weeks, for about five weeks, for about six weeks, for about sevenweeks, for about eight weeks, for about nine weeks, for about ten weeks,for about eleven weeks, for about twelve weeks, or for more than 12weeks.

Another important feature of the extruded implants is that differentconcentration levels of active agent may be established in the vitreoususing different doses of the active agent. As illustrated in FIG. 8, theconcentration of agent in the vitreous is significantly larger with the700 μg dexamethasone extruded implant than with the 350 μg dexamethasoneextruded implant. Different active agent concentrations are notdemonstrated with the compressed tablet implant. Thus, by using anextruded implant, it is possible to more easily control theconcentration of active agent in the vitreous. In particular, specificdose-response relationships may be established since the implants can besized to deliver a predetermined amount of active agent.

Applications

Examples of medical conditions of the eye which may be treated by theimplants and methods of the invention include, but are not limited to,uveitis, macular edema, macular degeneration, retinal detachment, oculartumors, fungal or viral infections, multifocal choroiditis, diabeticretinopathy, proliferative vitreoretinopathy (PVR), sympatheticopthalmia, Vogt Koyanagi-Harada (VKH) syndrome, histoplasmosis, uvealdiffusion, and vascular occlusion. In one variation, the implants areparticularly useful in treating such medical conditions as uveitis,macular edema, vascular occlusive conditions, proliferativevitreoretinopathy (PVR), and various other retinopathies.

Method of Implantation

The biodegradable implants may be inserted into the eye by a variety ofmethods, including placement by forceps, by trocar, or by other types ofapplicators, after making an incision in the sclera. In some instances,a trocar or applicator may be used without creating an incision. In apreferred variation, a hand held applicator is used to insert one ormore biodegradable implants into the eye. The hand held applicatortypically comprises an 18-30 GA stainless steel needle, a lever, anactuator, and a plunger.

The method of implantation generally first involves accessing the targetarea within the ocular region with the needle. Once within the targetarea, e.g., the vitreous cavity, the lever on the hand held device isdepressed to cause the actuator to drive the plunger forward. As theplunger moves forward, it pushes the implant into the target area.

Extrusion Methods

The use of extrusion methods allows for large-scale manufacture ofimplants and results in implants with a homogeneous dispersion of thedrug within the polymer matrix. When using extrusion methods, thepolymers and active agents that are chosen are stable at temperaturesrequired for manufacturing, usually at least about 50° C. Extrusionmethods use temperatures of about 25° C. to about 150° C., morepreferably about 60° C. to about 130° C.

Different extrusion methods may yield implants with differentcharacteristics, including but not limited to the homogeneity of thedispersion of the active agent within the polymer matrix. For example,using a piston extruder, a single screw extruder, and a twin screwextruder will generally produce implants with progressively morehomogeneous dispersion of the active. When using one extrusion method,extrusion parameters such as temperature, extrusion speed, die geometry,and die surface finish will have an effect on the release profile of theimplants produced.

In one variation of producing implants by extrusion methods, the drugand polymer are first mixed at room temperature and then heated to atemperature range of about 60° C. to about 150° C., more usually toabout 130° C. for a time period of about 0 to about 1 hour, more usuallyfrom about 0 to about 30 minutes, more usually still from about 5minutes to about 15 minutes, and most usually for about 10 minutes. Theimplants are then extruded at a temperature of between about 60° C. toabout 130° C., preferably at a temperature of between about 75° C. and110° C., and more preferably at a temperature of about 90° C.

In a preferred extrusion method, the powder blend of active agent andPLGA is added to a single or twin screw extruder preset at a temperatureof about 80° C. to about 130° C., and directly extruded as a filament orrod with minimal residence time in the extruder. The extruded filamentor rod is then cut into small implants having the loading dose of activeagent appropriate to treat the medical condition of its intended use.

DEX PS DDS

The present invention is based upon the discovery of an intraocular drugdelivery system which can address many of the problems associated withconventional therapies for the treatment of ocular conditions, such asposterior segment inflammation, including fluctuating drug levels, shortintraocular half-life, and prolonged systemic exposure to high levels ofcorticosteroids. The intraocular drug delivery system of the presentinvention encompasses use of dexamethasone as the active pharmaceuticalagent, in which case the intraocular drug delivery system of the presentinvention can be referred to as a Dexamethasone Posterior Segment DrugDelivery System (DEX PS DDS). The DEX PS DDS is intended for placementinto the posterior segment by a pars plana injection, a familiar methodof administration for ophthalmologists. The DEX PS DDS can be comprisedof a biodegradable copolymer, poly(lactic glycolic) acid (PLGA),containing micronised dexamethasone. The DEX PS DDS an releasedexamethasone, providing a total dose of approximately 350 or 700 μgover approximately 35 days. In comparison, other routes ofadministration (topical, periocular, systemic and standard intravitrealinjections) require much higher daily doses to deliver equivalent levelsof dexamethasone to the posterior segment while also exposing non-targetorgans to corticosteroids. Topical administration of 2 drops ofdexamethasone ophthalmic suspension 0.1% four times daily to both eyesis equivalent to almost 500 μg per day. Systemic doses may be as high as1,000 μg/kg/day (Pinar V. Intermediate uveitis. Massachusetts Eye & EarInfirmary Immunology Service.http://www.immunology.meei.harvard.edu/imed.htm. 1998; Weisbecker C A,Fraunfelder F T, Naidoff M, Tippermann R, eds. 1999 Physicians' DeskReference for Ophthalmology, 27th ed. Montvale, N.J.: Medical EconomicsCompany, 1998; 7-8, 278-279). With the DEX PS DDS, substantially lowerdaily doses of dexamethasone can be administered directly to theposterior segment compared to the doses needed with conventionaltopical, systemic, or intravitreal therapies, thereby minimizingpotential side effects. While releasing dexamethasone, the polymer cangradually degrades completely over time so there is no need to removethe DEX PS DDS after it's placement into the posterior segment of apatient eye.

To facilitate delivery of DEX PS DDS into the posterior segment of theeye, an applicator has been designed to deliver the DEX PS DDS directlyinto the vitreous. The DDS Applicator allows placement of the DEX PS DDSinto the posterior segment through a small hollow gauge needle, therebydecreasing the morbidity associated with surgery and pars planainjection at vitrectomy. The extruded DEX PS DDS is placed in theApplicator during the manufacturing of the sterile finished drugproduct. The DEX PS DDS Applicator System can be a single-use onlydevice.

700 μg and 350 μg Dexamethasone Posterior Segment Drug Delivery System(DEX PS DDS Applicator System) can be used in the treatment of, forexample, patients with macular oedema following central retinal veinocclusion or branch retinal vein occlusion.

Dexamethasone can be obtained from Aventis Pharma, Montvale, N.J.,U.S.A. The chemical name of dexamethasone ispregna-1,4-diene-3,20-dione-9-fluoro-11,17,21-trihydroxy-16-methyl-,(11□, 16□), and it's chemical structure can be representeddiagrammatically as follows:

Other characteristics of dexamethasone are: Molecular Formula: C₂₂H₂₉FO₅Molecular Weight: 392.47 Chirality/Stereochemistry: Dexamethasone has 8chiral centres and is optically active Description: White or almostwhite, crystalline powder pH and pKa: Dexamethasone has no ionisablegroups Melting Point: 253° C. to 255° C. Solubility: Water: practicallyinsoluble Ethanol: Sparingly soluble Methylene chloride: slightlysoluble

Further information on the physical and chemical properties ofdexamethasone is summarised in the current European Pharmacopoeia (Ph.Eur.).

An embodiment of our invention can be referred to as a DEX PS DDS. DEXPS DDS is an implant (a drug delivery system or DDS) for intravitreal(i.e. posterior segment, or PS) use, comprised of dexamethasone (i.e.DEX) (drug substance) and a polymer matrix of 50:50 poly(D,L-lactide-co-glycolide) PLGA, constituted of two grades of PLGA(50:50 PLGA ester and 50:50 PLGA acid). See Table 1 for details. Thisbiodegradable drug delivery system is designed to release the drugsubstance into the posterior segment of the eye over a 35-day period.DEX PS DDS can be implanted into the vitreous humour of the eye using anapplicator system.

Two dose levels, one containing 350 μg and one containing 700 μg ofdexamethasone, have been evaluated in a clinical trial. Both dose levelshave the same formulation as detailed in Table 2. They are preparedusing the same bulk and double extrusion process, but cut to differentlengths to obtain the appropriate dosage strength. TABLE 1 Qualitativecomposition of a sample DEX PS DDS Quality Component Standard FunctionDexamethasone Ph. Eur. Active ingredient 50:50 PLGA ester Allergan, Inc.Biodegradable extended release polymer matrix 50:50 PLGA acid Allergan,Inc. Biodegradable extended release polymer matrix

TABLE 2 Quantitative Composition of a sample DEX PS DDS (manufacturingbatch formula) 350 μg 700 μg Representative Formula number 80 gComponent 9635X 9632X Batch Quantity Dexamethasone 350 μg (60%) 700 μg(60%) 48 grams 50:50 PLGA  58 μg (10%) 116 μg (10%)  8 grams ester(hydrophobic) 50:50 PLGA 175 μg (30%) 350 μg (30%) 24 grams acid(hydrophilic)

The drug substance used in the DEX PS DDS is dexamethasone micronised.

DEX PS DDS can contain two excipients (i.e. non-active ingredients)which can be present as two different grades of the same biodegradablepolymer 50:50 Poly (D,L lactide-co-glycolide) (PLGA), which can besupplied by Boehringer Ingelheim: 50:50 PLGA ester and 50:50 PLGA acid.

Poly D,L lactide-co-glycolide has been used for more than 15 years inparenteral products and is a main component of absorbable sutures. Alist of some of the medical products commercially available is suppliedin Table 3. TABLE 3 List of commercial medical products containing PLGAManu- Drug Mode of Name facturer Substance Dosage form administrationVicryl ® Ethicon Suture used in ocular surgery Enantone ® TadekaLeuprorelin Microsphere Injection suspension (SC or IM) Prostap ® WyethLeuprorelin Microsphere Injection acetate suspension (SC or IM)Bigonist ® Aventis Buserelin Implant Injection (SC) Somatuline ®Beaufour Lanreotide Micro- Injection (IM) Ipsen acetate particle Pharmasuspension Sandostatin ® Novartis Octreotide Microsphere Injection (IM)acetate suspension Zoladex ® Astra Goserilin Implant Injection (SC)Zeneca acetate Risperdal Janssen- Risperidone Micro- Injection (IM)consta ® Cilag particle suspension Decapeptyl ® Ipsen TriptorelinInjection (IM) Gonapeptyl Ferring Triptorelin Micro- Injection Depot ®Pharma- acetate particle (SC or IM) ceutical suspension

PLGA exists in different grades depending on the ratio of lactide toglycolide and polymer chain ending. All PLGAs degrade via backbonehydrolysis (bulk erosion), and the degradation products, lactic acid andglycolic acid, are ultimately metabolised by the body into CO₂ and H₂O.The two PLGAs combination as presented in Table 2 was chosen in order toobtain a drug substance release over a 35-day period. General propertiesof the chosen PLGAs are presented in Table 4. TABLE 4 General propertiesof PLGAs 50:50 PLGA ester 50:50 PLGA acid Common Resomer RG 502, PLG,PLGA, Poly Resomer RG 502H, PLG acid end, PLGA acid Names(lactic-glycolic) acid, 50:50 Poly (D,L-lac- end, 50:50 Poly(D,L-lactide-co-glycolide) acid tide-co-glycolide), endPolylactic/Polyglycolic acid, Polyglactin 910 Structure

Where: Where: n = m n = m n = number of lactide repeating units n =number of lactide repeating units m = number of glycolide repeatingunits m = number of glycolide repeating units z = overall number oflactide-co-glycolide z = overall number of lactide-co-glycoliderepeating units repeating units CAS Number 34346-01-5 26780-50-7Empirical [(C3H4O2)x.(C2H2O2)y]CH3, [(C3H4O2)x.(C2H2O2)y]OH, Formula x:y= 50:50 x:y = 50:50 Description white to off white powder white to nearwhite powder

DEX PS DDS was designed to release dexamethasone in the posteriorsegment of the eye over an extended period of 35 days. This extendedrelease is achieved by including dexamethasone in a biodegradablepolymer matrix. The polymer chosen is 50:50 PLGA. The rate of release ismainly linked to the rate of degradation of the PLGA, depending onseveral factors such as molecular weight and weight distribution,lactide to glycolide ratio, polymeric chain endings, etc. The mechanismfor the degradation of PLGA is a hydrolysis triggered by the presence ofbody fluids i.e. vitreous humour in the case of DEX PS DDS.

Early formulations contained only one grade of PLGA (50/50 ratio withester end) custom synthesised. Subsequently, it was discovered that the“acid end” form of PLGA designated 50:50 PLGA acid, combined with the50:50 PLGA ester (equivalent to the initial PLGA), produced the desireddrug release profile. “Acid end” PLGA is slightly more hydrophilic andtherefore degrades faster in water. Both polymer backbones areidentical, but the polymerisation process used to produce acid end PLGAinvolves a different chain termination agent leading to carboxylicmoieties at the end of the polymer chains. During biodegradation of theimplant, the degradation products are the same for both polymers, i.e.lactic acid and glycolic acid. Details of the formulation proposed canbe found above. In addition, the stability of DEX PS DDS was evaluated.

EXAMPLES

The following examples serve to more fully describe the manner of usingthe above-described invention. It is understood that these examples inno way serve to limit the scope of this invention, but rather arepresented for illustrative purposes.

Example 1 Manufacture of Compressed Tablet Implants

Micronized dexamethasone (Pharmacia, Peapack, N.J.) and micronizedhydrophobic end 50/50 PLGA (Birmingham Polymers, Inc., Birmingham, Ala.)were accurately weighed and placed in a stainless steel mixing vessel.The vessel was sealed, placed on a Turbula mixer and mixed at aprescribed intensity, e.g., 96 rpm, and time, e.g., 15 minutes. Theresulting powder blend was loaded one unit dose at a time into asingle-cavity tablet press. The press was activated at a pre-setpressure, e.g., 25 psi, and duration, e.g., 6 seconds, and the tabletwas formed and ejected from the press at room temperature. The ratio ofdexamethasone to PLGA was 70/30 w/w for all compressed tablet implants.

Example 2 Manufacture of Extruded Implants

Micronized dexamethasone (Pharmacia, Peapack, N.J.) and unmicronizedPLGA were accurately weighed and placed in a stainless steel mixingvessel. The vessel was sealed, placed on a Turbula mixer and mixed at aprescribed intensity, e.g., 96 rpm, and time, e.g., 10-15 minutes. Theunmicronized PLGA composition comprised a 30/10 w/w mixture ofhydrophilic end PLGA (Boehringer Ingelheim, Wallingford, Conn.) andhydrophobic end PLGA (Boehringer Ingelheim, Wallingford, Conn.). Theresulting powder blend was fed into a DACA Microcompounder-Extruder(DACA, Goleta, Calif.) and subjected to a pre-set temperature, e.g.,115° C., and screw speed, e.g., 12 rpm. The filament was extruded into aguide mechanism and cut into exact lengths that corresponded to thedesignated implant weight. The ratio of dexamethasone to total PLGA(hydrophilic and hydrophobic end) was 60/40 w/w for all extrudedimplants.

Example 3 Method for Placing Implants into the Vitreous

Implants were placed into the posterior segment of the right eye of NewZealand White Rabbits by incising the conjunctiva and sclera between the10 and 12 o'clock positions with a 20-gauge microvitreoretinal (MVR)blade. Fifty to 100 μL of vitreous humor was removed with a 1-cc syringefitted with a 27-gauge needle. A sterile trocar, preloaded with theappropriate implant (drug delivery system, DDS), was inserted 5 mmthrough the sclerotomy, and then retracted with the push wire in place,leaving the implant in the posterior segment. Sclerae and conjunctivaewere than closed using a 7-0 Vicryl suture.

Example 4 In Vivo Release of Dexamethasone from 350 μg DexamethasoneCompressed Tablet Implants

Example 4 demonstrates the high initial release but generally lowerintravitreal concentration of dexamethasone from compressed tabletimplants as compared to extruded implants. The 350 μg compressed tabletimplant (350T) was placed in the right eye of New Zealand White Rabbitsas described in Example 3. Vitreous samples were taken periodically andassayed by LC/MS/MS to determine in vivo dexamethasone deliveryperformance. As seen in FIG. 1, dexamethasone reached detectable meanintravitreal concentrations from day 1 (142.20 ng/ml) through day 35(2.72 ng/ml), and the intravitreal concentration of dexamethasonegradually decreased over time.

In addition to the vitreous samples, aqueous humor and plasma sampleswere also taken. The 350T showed a gradual decrease in aqueous humordexamethasone concentrations over time, exhibiting a detectable meandexamethasone aqueous humor concentration at day 1 (14.88 ng/ml) throughday 21 (3.07 ng/ml), as demonstrated in FIG. 3. The levels ofdexamethasone in the aqueous humor strongly correlated with the levelsof dexamethasone in the vitreous humor, but at a much lower level(approximately 10-fold lower). FIG. 4 shows that only trace amounts ofdexamethasone was found in the plasma.

Example 5 In Vivo Release of Dexamethasone from 350 μg DexamethasoneExtruded Implants

Example 5 demonstrates the lower initial release and generally moresustained intravitreal concentration of dexamethasone from extrudedimplants. The 350 μg extruded implant (350E) was placed in the right eyeof New Zealand White Rabbits as described in Example 3. Vitreous sampleswere taken periodically and assayed by LC/MS/MS to determine in vivodexamethasone delivery performance. Referring to FIG. 1, 350E showeddetectable mean vitreous humor concentrations on day 1 (10.66 ng/ml)through day 28 (6.99 ng/ml). The 350T implant had statisticallysignificant higher dexamethasone concentrations on day 1 (p=0.037) whilethe 350E had a statistically significant higher dexamethasone level onday 21 (p=0.041).

In addition to the vitreous samples, aqueous humor and plasma sampleswere also taken. In FIG. 3, the 350E showed detectable meandexamethasone aqueous humor concentrations at day 1 (6.67 ng/ml) throughday 42 (2.58 ng/ml) with the exception of day 35 in which the valueswere below the quantification limit. On the whole, the levels ofdexamethasone in the aqueous strongly correlated with the levels ofdexamethasone in the vitreous humor, but at a much lower level(approximately 10-fold lower). FIG. 4 demonstrates that only a traceamount of dexamethasone was found in the plasma.

Example 6 In Vivo Release of Dexamethasone from 700 μg DexamethasoneCompressed Tablet Implants

Example 6 also shows the high initial release and generally lowerintravitreal concentration of dexamethasone from compressed tabletimplants. The 700 μg compressed tablet dosage form (700T) was placed inthe right eye of New Zealand White Rabbits as described in Example 3.Vitreous samples were taken periodically and assayed by LC/MS/MS todetermine in vivo dexamethasone delivery performance. As seen in FIG. 5,the 700T reached detectable mean dexamethasone vitreous humorconcentrations at day 1 (198.56 ng/ml) through day 42 (2.89 ng/ml), anda gradual decrease in the intravitreal dexamethasone concentration overtime.

In addition to the vitreous samples, aqueous humor and plasma sampleswere also obtained. As seen in FIG. 6, the 700T exhibited a gradualdecrease in aqueous humor dexamethasone concentrations over time, andreached detectable mean dexamethasone aqueous humor concentrations atday 1 (25.90 ng/ml) through day 42 (2.64 ng/ml) with the exception ofday 35 in which the values were below the quantification limit. Thelevels of dexamethasone in the aqueous humor strongly correlated withthe levels of dexamethasone in the vitreous humor, but at a much lowerlevel (approximately 10-fold lower). FIG. 7 demonstrates that only atrace amount of dexamethasone was found in the plasma.

Example 7 In Vivo Release of Dexamethasone from 700 μg DexamethasoneExtruded Implants

Example 7 also illustrates the lower initial release and generallyhigher intravitreal concentration of dexamethasone from extrudedimplants. The 700 μg extruded implant (700E) was placed in the right eyeof New Zealand White Rabbits as described in Example 3. Vitreous sampleswere taken periodically and assayed by LC/MS/MS to determine in vivodexamethasone delivery performance. As seen in FIG. 5, the 700E had amean detectable vitreous humor concentration of dexamethasone from day 1(52.63 ng/ml) through day 28 (119.70 ng/ml).

In addition to the vitreous samples, aqueous humor and plasma sampleswere also taken. As seen in FIG. 6, the 700E reached a detectable meanaqueous humor concentration on day 1 (5.04 ng/ml) through day 28 (5.93ng/ml). The levels of dexamethasone in the aqueous strongly correlatedwith the levels of dexamethasone in the vitreous humor, but at a muchlower level (approximately 10-fold lower). FIG. 7 demonstrates that onlya trace amount of dexamethasone was found in the plasma.

Example 8 Extrusion Methods for Making an Implant

1. DEX PS DDS implants were made by a tabletting process, by a singleextrusion process and by a double extrusion process.

The excipients (polymers) used for the DEX PS DDS implant made were twogrades of 50:50 Poly (D,L lactide co glycolide) ester end and acid end.Both excipients were a pharmaceutical grade of non-compendial material.

The preferred specifications of three batches of both 50:50 Poly PLGAester used to make implants are shown in Table A. The preferredspecifications of three batches of 50:50 Poly PLGA acid use to makeimplants are shown in Table B. TABLE A Preferred Specifications for50:50 PLGA ester Tests Specifications 1001933 1004907 1004925Appearance: Colour and shape White to off white Off white Off white Offwhite Odour Odourless to almost almost almost almost odourless odourlessodourless odourless Identification 1^(H)-NMR spectra conforms conformsconforms conforms to reference Polymer composition DL-Lactide units 48to 52% 51 51 51 Glycolide units 52 to 48% 49 49 49 Inherent viscosity0.16 to 0.24 dl/g  0.24  0.19  0.19 Water □0.5% Conforms ConformsConforms Residual monomers DL-lactide □0.5% Conforms Conforms ConformsGlycolide □0.5% Conforms Conforms Conforms Residual solvents Acetone□0.1% Conforms Conforms Conforms Toluene □0.089% Conforms ConformsConforms Total □0.1% Conforms Conforms Conforms Tin □100 ppm 30 31 35Heavy metals □10 ppm Conforms Conforms Conforms Sulphated ashes □0.1%Conforms Conforms Conforms

TABLE B Preferred Specifications for 50:50 PLGA acid Test Specification1006825 1008386 1009848 Appearance: Colour and shape White to nearlyWhite White Off white white Odour Odourless to nearly OdourlessOdourless Almost odourless odourless Identification 1^(H)-NMR spectraConforms Conforms Conforms conforms to reference Polymer compositionDL-Lactide units 48 to 52% 51 51 51 Glycolide units 52 to 48% 49 49 49Inherent viscosity 0.16 to 0.24 dl/g 0.19 0.19 0.19 Water □0.5% ConformsConforms Conforms Residual monomers DL-lactide □0.5% Conforms ConformsConforms Glycolide □0.5% Conforms Conforms Conforms Residual solventsAcetone □0.1% Conforms Conforms Conforms Toluene □0.089% ConformsConforms Conforms Tin □200 ppm 149 83 141 Heavy metals □10 ppm ConformsConforms Conforms Sulphated ashes □0.1% Conforms Conforms Conforms Acidnumber □6.5 mg_(KOH)/g 11 9 12

Preferred Specifications of Polymers Use to Make Implants

Polymer composition: It was determined that the ratio of lactide toglycolide is essential for the kinetic of degradation of the polymer andhence the dexamethasone release profile of the implant. It wascontrolled in a 48% to 52% (wt %) range to ensure consistency of activeagent release.

Inherent viscosity: the inherent viscosity is essential for the kineticsof degradation of the polymer and hence the dexamethasone releaseprofile of the implant. It is a measure of the size of the polymerbackbone and the size distribution (i.e. molecular weight and weightdistribution). It was controlled in a 0.16 to 0.24 dl/g range to ensureconsistency of release.

Water: The moisture content of the polymer influences its stabilityduring the shelf life and is a facilitating factor for thebiodegradation of the polymer matrix. It was controlled below 0.5% toensure stability of the excipients as well as the drug substance(dexamethasone) and to ensure consistency of the (dexamethasone) releaseprofile.

Residual monomers: residual monomers indicate the completion of thesynthesis of the polymer and was controlled below 0.5 wt. %.

Residual solvents:

-   -   Acetone was controlled to below 0.1 wt. %    -   Toluene was controlled to be kept below 0.0890 wt. %.

Acid number: the acid number measures the number of chain ends in thePLGA acid polymer. The number of acid polymer endings facilitates theingress of moisture upon injection of the implant and influences therelease profile of the implant. It was controlled to be higher than 6.5mg _(KOH)/g to ensure consistency of release profile.

Preferred Dexamethasone Characteristics

The particle size and particle size distribution of the dexamethasone isregarded as a critical parameter for the homogeneity of the DEX PS DDS.A preferred dexamethasone particle size distribution has at least 75% ofthe particles of dexamethasone smaller than (i.e. diameter less than) 10μm. A more preferred dexamethasone particle size distribution has atleast 99% of the particles of dexamethasone smaller than (i.e. diameterless than) 20 μm. We found that use of such small particles ofdexamethasone in the implant provides for a more uniform distribution ofthe active agent in the implant (i.e. no clumping) which leads to a moreuniform release of the active agent from the implant upon implantationof the implant.

In addition to all the Ph. Eur. tests for dexamethasone, additionaltests were performed on the dexamethasone using a particle size analyserand an additional analytical method, so as to ensure that thedexamethasone used in the DEX PS DDS had the preferred or the morepreferred particle size and particle size distribution.

In our invention dexamethasone a particle size and particle sizedistribution is an important factor because homogeneity of thedexamethasone affects release characteristics.

It is additionally preferred that the dexamethasone used in the presentinvention comprise □[1% of total impurities, including □0.50% ofdexamethasone acetate, □0.25% of bethamethasone, □0.25% of 3 keto delta4 derivative and □0.10% of any other impurity.

A representative formula for a typical 80 g manufacturing batch (used tomake an implant manufactured by the tabletting, single extrusion ordouble extrusion process) is provided in Table 2. For the 350 μg and 700μg dosages, the bulk manufacturing and terminal sterilisation processesare identical.

A flow diagram of the three different manufacturing processes is shownby FIG. 11.

2. A single extrusion process was used to made an implant. In acontinuous extrusion, single extrusion manufacturing process, themicronised dexamethasone and un-micronised polymer was blended, beforebeing loaded into a twin-screw compound extruder, and then subjected toa set temperature and screw speed. The filament was extruded into aguide mechanism and cut into exact lengths that correspond to thecorrect DEX PS DDS weight. This continuous extrusion process was morecontrollable and more predictable than the tabletting process. This isillustrated in the in vitro release profiles of the DEX PS DDS as showin FIG. 12.

Four lots of 700 μg DEX PS DDS, two manufactured by the tablettingprocess and two by the single extrusion process were studied. With thesingle extrusion process the only difference between the two doses isthat the 350 μg dose filament is cut from the same extrudate (sameformulation) as 700 μg dose filament but is half as long. At 5 timepoints, over a 28-day period, 12 DEX PS DDS units from each lot weretested. The standard deviations for the mean dexamethasone release rateswere found larger for the two tabletted lots than for the two extrudedlots. A three-fold reduction in standard deviations across the releaseprofile was observed with the extruded versus the tabletted product. Inaddition, the initial burst release is reduced with implantsmanufactured by a single extrusion process, as compared to implants madeby a tabletting process.

These results were confirmed in a GLP in vivo pharmacokinetics study inrabbits comparing the release of dexamethasone from the tabletted andthe extruded DEX PS DDS. It was shown that the tabletted and the singleextruded DEX PS DDS release the same amount of dexamethasone over thesame period, providing approximately a 35-day delivery.

To further characterise and compare the DEX PS DDS manufactured by thetabletting and single extrusion processes, scanning electron microscope(SEM) photographs were taken to assess physical appearance. FIG. 13shows that the single extruded DEX PS DDS is more uniform than was thetabletted implant. It was found that not only is this gives a moreconsistent in vitro release profile from the single extruded implant,but also with its increased resistance to crushing. Using a textureanalyser it was shown that a 3-fold increase in force (1200 g comparedto 400 g) was required to crush a single extruded implant compared to atabletted one. This demonstrates that the extruded product is more ableto withstand handling.

Additionally, it was determined that the DEX PS DDS made by singleextrusion and by double extrusion processes is stable during a minimumof 12 months (and for as long as 18-24 months) when stored at 25° C./60%RH and a minimum of 6 months at 40° C./75% RH. Stability was determinedbased upon dexamethasone potency, dexamethasone impurities (acid,ketone, aldehyde and total impurities), moisture content, applicatoractuation force, implant fracture force/fracture energy and in vitrodissolution dexamethasone release profile and sterility.

3. The inventors improved the single extrusion process by (1)micronising the polymers prior to blending and (2) adding a secondextrusion after pelletisation of the first extruded filament. When both50:50 PLGA acid and 50:50 PLGA ester were micronised an acceptable DEXPS DDS homogeneity was obtained. Homogeneity promotes a more even andregular dissolution of the polymer and release of the dexamethazoneactive agent. The PLGAs were milled using an air jet process. FIG. 14presents batch-to-batch versus in-batch variability from batches made ofmilled (i.e. micronised) and un-milled (i.e. unmicronized) PLGAs. Itclearly demonstrates that the double extrusion process allows bettercontrol, especially where in-batch variability was reduced from a 94.7%LC to 107.0% LC range (unmilled PLGAs) to a 98.9% LC to 101.5% LC range(milled PLGAs. “LC” means label claim (a regulatory term), that is theamount of dexamethasone present in the implant (350 μg or 700 μg), asmeasured by various in vitro assays, such as by HPLC.

Single and double extrusion processes were compared. As shown by FIG. 15implants made by a double extrusion process had released about 60% ofthe dexamethasone by day 14, while the single extrusion implants hadreleased about 40% of its dexamethasone load by day 14, although totaldexamethasone released was comparable by day 21. Therefore, where morerelease of dexamethasone is desired sooner, the double extrusion processis a preferred process for making the DEX PS DDS. A double extrusionprocess also provides for a higher yield of the desired filamentimplant, i.e. with a uniform distribution of dexamethasone throughoutthe implant polymer.

A detailed manufacturing schematic flow diagram for the double extrusionimplant is provided by FIG. 16. The major equipment used in themanufacture of DEX PS DDS is listed in Table C. TABLE C Major EquipmentUsed in the Manufacture of DEX PS DDS Step Purpose Equipment Description1 Milling both PLGAs Jet Mill 2 Powder blending Shaker 3 First extrusionExtruder and Force Feeder, Puller Assembly and Filament Cutter 4Pelletising Stainless steel ball and bottle Shaker 5 Second extrusionExtruder and Force Feeder, Puller Assembly and Filament Cutter 6Automated DDS cutting and Guillotine Cutter and inspection procedureVision Inspection System 7-8 Applicator Assembly Applicator loadingfixture and Heat sealer

4. The specifics of the double extrusion process used are as follows

(a) Milling of PLGAs (Resomers RG502 and RG502H)

30 grams of RG502 (50:50 PLGA ester) were milled using the Jet-Mill (avibratory feeder) at milling pressures of 60 psi, 80 psi and 80 psi forthe pusher nozzle, grinding nozzle, and grinding nozzle, respectively.Next, 60 grams of RG502H were milled using the Jet-Mill at millingpressure of 20 psi, 40 psi and 40 psi for the pusher nozzle, grindingnozzle, and grinding nozzle, respectively. The mean particle size ofboth RG502 and RG502H was measured using a TSI 3225 Aerosizer DSPParticle Size Analyzer. Preferably, both milled polymers must have amean particle size of no greater than 20 um.

(b) Blending of PLGAs and Dexamethasone

48 grams of dexamethasone, 24 grams of milled RG502H and 8 grams ofmilled RG502 were blended using the Turbula Shaker set at 96 RPM for 60minutes.

(c) First Extrusion

(1) All 80 grams of the blended dexamethasone/RG502H/RG502 mixture wasadded to the hopper of a Haake Twin Screw Extruder. The Haake extruderwas turned on and set the following parameters:

-   -   Barrel Temperature: 105 degrees C.    -   Nozzle Temperature: 102 degrees C.    -   Screw Speed: 120 RPM    -   Feed Rate Setting: 250    -   Guide Plate Temperature: 50-55 degrees C.    -   Circulating water bath: 10 degrees C.

(2) Filament were collected. The first filament comes out about 15-25minutes after the addition of the powder blend. Discard the first 5minute of extruded filaments. Collecting the remaining filaments untilexhaustion of extrudates; this normally takes 3-5 hours.

(d) Pelletization

The filaments from step 3 above were pelletized using the Turbula Shakerand one 19 mm stainless steel ball set at 96 RPM for 5 minutes.

(e) Second Extrusion

(1) All pellets were added into the same hopper and the Haake extruderwas turned on.

The following parameters were set on the Haake extruder:

-   -   Barrel Temperature: 107 degrees C.    -   Nozzle temperature: 90 degrees C.    -   Screw speed: 100 RPM    -   Guide Plate Temperature: 60-65 degrees C.    -   Circulation water bath: 10 degrees C.

(2) All extruded filaments were collected until exhaustion ofextrudates. This normally takes about 3 hours.

(f) Processing of Bulk Filament to Dosage strengths—350 μg or 700 ∞g

DEX PS DDS was be prepared as 350 μg or 700 μg dosage forms by cuttingthe filaments to the appropriate length.

(g) Insertion of DEX PS DDS into the Applicator

The DEX PS DDS was inserted into the Applicator System during theapplicator assembly process. All operations took place in a Class 10 000clean room.

(h) Packaging of DEX PS DDS Applicator System

The assembled DEX PS DDS Applicator System was placed into a foil pouchcontaining a small bag of desiccant and heat-sealed. Samples forpre-sterilisation bioburden testing were taken prior to step 9.

(i) Gamma Radiation Sterilization of DEX PS DDS Applicator System

The sealed foil pouches containing the finished DEX PS DDS ApplicatorSystem and a small desiccant bag were placed into a cardboard box andthe box sealed. Terminal sterilisation of these product containing boxeswas accomplished by exposure to a dose within the range of 25-40 kGy ofgamma-radiation. Samples from each batch were tested for sterilityaccording to Ph. Eur. and USP requirement.

(j) Labelling of DEX PS DDS Applicator

The single and double extruded implants had the preferredcharacteristics shown by Tables D and E, respectively. TABLE D InProcess Controls results for the first extrusion Batch Number 03J00103H004 03M001 Batch size Parameter Specifications 80 g 80 g 80 gFilament density 0.85 to 1.14 g/cm³ 1.03 1.01 1.04 Uniformity 85.0 to115.0%⁽¹⁾ 99.3 100.5 98.7 Potency 97.0 to 103.0% 100.1 100.0 99.8 labelstrength Degradation □1.5% total 0.2 0.2 0.2 products □0.75% acid ND NDND □0.75% ketone □0.08 □0.10 □0.13 □0.75% aldehyde □0.15 □0.10 □0.12⁽¹⁾Percentage of target weight

TABLE E In Process Control results for the second extrusion Batch number03J001 03H004 03M001 Batch size Parameter Specifications 80 g 80 g 80 gAppearance White to off white pass pass pass Filament density 1.10 to1.30 g/cm³ 1.18 1.13 1.19 Diameter □80% within 0.0175 to 0.0185 inch 100100 100 Fracture force □2 g 9.88 9.39 9.52 Fracture energy □0.9 μJ 5.884.54 4.64 Moisture □1.0% 0.4 0.4 0.4 Foreign particulate No visibleforeign materials Pass Pass Pass Insoluble mater Particle count (forinformation Diameter □10 μm 17 26 2.6 only) Diameter □25 μm 0.5 1 0Dexamethasone Positive for dexamethasone positive positive positiveidentity Potency 95.0 to 105.0% label strength 98.5 101.2 99.9Degradation □2% total 1.1 0.6 1.0 products □0.5% acid ND ND ND □1.0%ketone 0.4 0.2 0.4 □1.0% aldehyde 0.7 0.4 0.5 Dexamethasone See Table2.1.P.5.1-1 Pass Pass Pass release Uniformity 85.0-115.0% Label Strength(LS) 97.0% 97.1% 98.0% Stage 1 (n = 10): If one unit is outside therange and all values all values all values between 75% and 125% LS orRSD □6.0%, test within within within 20 more units. range range rangeStage 2 (n = 20): pass if no more than 1 unit is outside the range, andis between 75% and 125% LS, and the RSD □7.8%.

Table F sets forth further preferred specifications for both the DEX PSDDS implant and the applicator. TABLE F Preferred specificationsAttribute Specifications Implant appearance White to off-white, rodshaped Drug Delivery System (DDS), essentially free of foreign matter.Fracture Force Minimum 2.0 g Energy Minimum 0.85 μjoule Moisture contentNo more than 1% Foreign particulates No visible foreign materialInsoluble matter Record particle count for information only (diameter□10 μm and □25 μm) Dexamethasone identity Positive for dexamethasoneDexamethasone potency 90.0 to 110.0% LC Impurities Dexamethasone acidnot greater than 0.5% HPLC area Dexamethasone ketone not greater than1.0% HPLC area Dexamethasone aldehyde not greater than 1.0% HPLC areaTotal degradation not greater than 2% HPLC area Weight Range 700 μgdose: 1.050 mg to 1.284 mg (1.167 mg +/− 10%) 350 μg dose: 0.525 mg to0.642 mg (0.583 mg +/− 10%) Content uniformity 85% to 115% Label ClaimIn vitro Dissolution test (% Ranges: 24 hours: not greater than 10.0% oftotal amount of 7 days: not greater than 30.0% dexamethasone released)14 days: 25.0% to 85.0% 21 days: not less than 50% Applicator Actuationforce No more than 5.0 lbs required

Implants and Applicators made as set forth above were found to be withinthe parameters of the preferred specifications.

Preferred Applicator A preferred applicator to use to implant the DEX PSDDS is shown in international patent publication WO 2004/026106,published Apr. 1, 2004. The applicator was designed to facilitate theinsertion of the implant in the posterior segment of the eye. Theimplant is housed in the needle of the applicator. The applicator isdesigned to fit comfortably into the hand of the physician, and to allowfor single-handed operation. It is similar in size to retinal forceps,measuring 165 mm in length by 13 mm in width. FIG. 17 provides acut-away side view of the applicator illustrating the typical functionsand positions of all the elements.

As the lever is depressed, it applies a force on the linkage, whichcollapses and moves the plunger forward into the needle, pushing the DEXPS DDS into the posterior chamber of the eye. Once the DEX PS DDS isdelivered, the lever then latches within the Applicator housing tosignal use and prevent any reuse. The needle used is a 22-gaugethin-wall hypodermic needle. A silicone o-ring, is placed into a slot inthe needle to retain the DEX PS DDS within the needle and remainsoutside the eye, in contact with the conjunctiva. To ensure that air isnot introduced into the eye, the applicator has been designed to vent. Asmall gap between the DEX PS DDS and inner needle wall allows air tomove back through and out of the needle as the DEX PS DDS is beingdelivered. The small size of this gap prevents fluid from flowing out ofthe eye through the needle. The components of the Applicator that maycontact the patient during use are the plunger, needle and o-ring. Theplunger and needle are manufactured from materials of knownbiocompatibility, and with a history of human use. Biocompatibility ofthe o-ring was evaluated through cytotoxicity testing.

The applicator is packed with desiccant in a pouch designed to protectthe implant from humidity. The packaged implant in the applicator isthen sterilised by gamma irradiation. The pouch also ensures that theproduct remains sterile during the shelf life.

The DEX PS DDS is terminally sterilised by gamma irradiation, in itsapplicator as presented packed in the foil pouch, using a 25 to 40 kGydose. Terminal sterilisation process steam sterilisation (autoclaving)is not used because the polymers used for the controlled release areextremely sensitive to moisture and heat and degrade even withnon-compendial low temperature sterilisation cycles.

The DEX PS DDS Applicator System is a sterile, single use applicatorintended to deliver one DEX PS DDS. The DEX PS DDS is loaded into theneedle of the Applicator during the assembly process. It is thenpackaged in a foil pouch with desiccant and terminally sterilised bygamma irradiation.

All publications, patents, and patent applications cited herein arehereby incorporated by reference in their entirety for all purposes tothe same extent as if each individual publication, patent, or patentapplication were specifically and individually indicated to be soincorporated by reference. Although the foregoing invention has beendescribed in some detail by way of illustration and example for purposesof clarity of understanding, it will be readily apparent to those ofordinary skill in the art in light of the teachings of this inventionthat certain changes and modifications may be made thereto withoutdeparting from the spirit and scope of the appended claims.

1. A bioerodible implant for treating an ocular condition comprising anactive agent dispersed within a biodegradable polymer matrix, wherein atleast about 75% of the particles of the active agent have a diameter ofless than about 10 μm.
 2. The implant of claim 1, wherein at least about99% of the particles of the active agent have a diameter of less thanabout 20 μm.
 3. The bioerodible implant of claim 1 wherein the activeagent is selected from the group consisting of ace-inhibitors,endogenous cytokines, agents that influence basement membrane, agentsthat influence the growth of endothelial cells, adrenergic agonists orblockers, cholinergic agonists or blockers, aldose reductase inhibitors,analgesics, anesthetics, antiallergics, anti-inflammatory agents,steroids, antihypertensives, pressors, antibacterials, antivirals,antifungals, antiprotozoals, anti-infective agents, antitumor agents,antimetabolites, and antiangiogenic agents.
 4. The bioerodible implantof claim 1 wherein the active agent comprises an anti-inflammatory agentor any derivative thereof.
 5. The bioerodible implant of claim 1 whereinthe active agent comprises a steroidal anti-inflammatory agent or anyderivative thereof.
 6. The bioerodible implant of claim 4 wherein theactive agent is selected from the group consisting of cortisone,dexamethasone, fluocinolone, hydrocortisone, methylprednisolone,prednisolone, prednisone, triamcinolone, and any derivative thereof. 7.The bioerodible implant of claim 1 wherein the active agent comprisesdexamethasone.
 8. The bioerodible implant of claim 1 wherein the implantis sized for implantation in an ocular region.
 9. The bioerodibleimplant of claim 8 wherein the ocular region is selected from the groupconsisting of the anterior chamber, the posterior chamber, the vitreouscavity, the choroid, the suprachoroidal space, the conjunctiva, thesubconjunctival space, the episcleral space, the intracorneal space, theepicorneal space, the sclera, the pars plana, surgically-inducedavascular regions, the macula, and the retina.
 10. The bioerodibleimplant of claim 9 wherein the ocular region is the vitreous cavity. 11.A bioerodible implant for treating an ocular condition comprising asteroid active agent dispersed within a biodegradable polymer matrix,wherein at least about 75% of the particles of the steroid active agenthave a diameter of less than about 20 μm.
 12. The bioerodible implant ofclaim 11 wherein the steroid active agent is selected from the groupconsisting of cortisone, dexamethasone, fluocinolone, hydrocortisone,methylprednisolone, prednisolone, prednisone, triamcinolone, and anyderivative thereof.
 13. The bioerodible implant of claim 12 wherein thesteroid active agent comprises dexamethasone.
 14. A method for making abioerodible implant for treating an ocular condition of the eye, themethod comprising a plurality of extrusions of a biodegradable polymer.15. The method of claim 14 further comprising the step of milling thebiodegradable polymer prior to the extrusion.
 16. The method of claim14, wherein the biodegradable polymer comprisespoly(lactic-co-glycolic)acid (PLGA) copolymer.
 17. The method of claim16 wherein the ratio of lactic to glycolic acid monomers is about 50/50weight percentage.
 18. The bioerodible implant of claim 16 wherein thePLGA copolymer is about 20 to about 90 weight percent of the bioerodibleimplant.
 19. The method of claim 18 wherein the PLGA copolymer is about40 percent by weight of the bioerodible implant.
 20. A method for makinga bioerodible implant for treating an ocular condition, the methodcomprising the steps of: (a) milling a biodegradable polymer; (b)blending the milled biodegradable polymer and particles of an activeagent, to thereby obtain a blended mixture of the milled biodegradablepolymer and the particles of the active agent, wherein at least about75% of the particles of the active agent have a diameter of less thanabout 20 μm; (c) carrying out a first extrusion of the blended mixture,to thereby obtain a first extrusion product; (d) pelletizing the firstextrusion product, and; (e) carrying out a second extrusion of thepelletized first extrusion product, thereby obtaining a bioerodibleimplant for an ocular condition.
 21. A bioerodible implant for treatingan ocular condition made by the method of claim 14.